A Phase 1/2, Open-label Study of Nivolumab Monotherapy or Nivolumab Combined With Ipilimumab in Subjects With Advanced or Metastatic Solid Tumors
Phase: PHASE1
Conditions: Advanced or Metastatic Solid Tumors
Sponsor: Bristol-Myers Squibb



Clinical Protocol
CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Revised Protocol No.: 07d
Date: 03-Oct-2019
2
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
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Clinical Protocol
CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Revised Protocol No.: 07d
Date: 03-Oct-2019
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 07d -
USA
03-Oct-2019

Updated personnel with Medical Monitor 

Added live/attenuated vaccines and complementary medications
(eg, herbal supplements) to Prohibited and/or Restricted Treatments 

Clarified tumor assessment language

Updated Appendix 2 (Management Algorithms) with addition of 
myocarditis AE management algorithm to reflect update in the 
Nivolumab IB

Added survival visits time window (from Administrative 
letter 5, dated 27-Aug-2018)
Revised 
Protocol 07c -
USA
27-Jan-2017
Incorporates Amendment 16
Amendment 16
27-Jan-2017
To remove one inclusion criteria for the bladder cohort
Revised 
Protocol 07b -
USA
27-Oct-2016
Incorporates Amendment 14 and 15
Amendment 15
27-Oct-2016
•
To clarify that for the pancreatic cohort, shorter infusion times of 
nivolumab and ipilimumab will be implemented.
Amendment 14
26-Oct-2016
•
To expand the bladder cohort (Nivolumab 1 mg/kg combined with 
Ipilimumab 3 mg/kg).
Revised 
Protocol 07a -
USA
11-Aug-2016
Incorporates Amendment 13
Amendment 13
11-Aug-2016
•
Implementation of the additional pancreatic cohort treated with a 
combination of nivolumab, ipilimumab and cobimetinib.
Revised 
Protocol 07
10-Aug-2016
Incorporates Amendment 12
Amendment 12
10-Aug-2016
•
Changed the primary objective for the expansion SCLC cohort to 
require evaluation by BICR.
•
Removed the limitation of enrolling subjects with 1 or 2 prior lines of 
therapy in the same fixed proportion of 50% for each subgroup.
•
Added permission to use palliative radiation therapy to other non-
target lesions
•   Added permission to use surgical resection or stereotactic 
radiotherapy following initial response or long-term stable disease
•   Limited PK and immunogenicity samples collection up to 2 years
•   Updated Appendix 2 (Management Algorithms) to reflect updates in 
the nivolumab IB.
• Added Appendix 6 (Methods of Contraception) to reflect updates in the 
nivolumab IB.
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Clinical Protocol
CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Revised Protocol No.: 07d
Date: 03-Oct-2019
4
Document
Date of Issue
Summary of Change
Revised 
Protocol 06
18-Nov-2015
Incorporates Amendment 11
Amendment 11
18-Nov-2015
•
Clarification regarding the local lab assessment timing was added.
•
For Ovarian Cancer cohort, specification of minimum tissue sample 
collection for ovarian cancer due to the fact that additional analyses of 
Homologous Recombination Deficiency (HRD) status and Breast 
Cancer genes 1 and 2 (BRCA1 and BRCA2) mutation status will be 
conducted in this cohort.
•
For SCLC expansion cohort, exact language regarding number of 
prior treatment lines added for consistency with Section 3.1.5 and the 
study synopsis.
•
Specification of the crossover option: This option refers only to the 
original cohorts and not the new cohorts enrolled under or after 
Amendment 09 implementation.
•
To increase flexibility in obtainment of tumor samples, for subjects 
with only one site of measurable disease tumor sampling criteria for 
biopsies from NOT the only site of measurable disease were widened.
•
Clarification regarding requirement for baseline CT and MRI brain 
scans.
•
Updated biomarker timepoint requirements for Day 8, 15, 22 and 29 
sample collections.
•
For Ovarian Cancer cohort, due to the low risk of development of new 
safety signals on the combination arms confirmed by the additional 
information from the combination studies in melanoma, lung, renal 
cell carcinoma, and glioblastomas as well as the clinical study with 
ipilimumab 10 mg/kg monotherapy in ovarian cancer, which did not 
reveal any new safety signals, the Safety Evaluation Phase will be 
removed. Ovarian cancer subjects will be followed for related 
toxicities and decisions to stop enrollment will be made on an ongoing 
basis.
Revised 
Protocol 05
23-Sep-2015
Incorporates Amendment 10
Amendment 10
23-Sep-2015
• Clarification regarding PK/immunogenicity sampling and pregnancy 
test was added.
• Regimen NI2c was added for treatment of ovarian cancer, including 
PK/immunogenicity and pregnancy sampling clarifications
• Safety assessments in all indications and treatment cohorts is 
harmonized: D4 W2 and W5 safety assessments are deleted from the 
NI cohorts consistent with nivolumab monotherapy and nivolumab 3 
mg/kg Q2W/ipilimumab 1 mg/kg Q6W cohorts
• For options of treatment beyond progression and crossover to NI 
combination arm, specification of unequivocal disease progression 
based on non-target lesions only is added
• Specification of response to platinum-based therapy in SCLC and 
Ovarian cancer is added to appendices
• Regimen NI2c was removed from the flowchart for Bladder cancer 
(correction)
• For SCLC expansion cohort, clarification of stratified randomization is 
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Clinical Protocol
CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Revised Protocol No.: 07d
Date: 03-Oct-2019
5
Document
Date of Issue
Summary of Change
added
• For subjects from NI combination who undergo a re-exposure if they 
achieved an initial objective response (PR or CR) or stable disease of > 
3 months and had a subsequent documented progression, an option to 
continue treatment with nivolumab monotherapy if ipilimumab 
treatment was stopped due to toxicity is added
Revised 
Protocol 04
06-Aug-2015
Incorporates Amendment 09
Amendment 09
06-Aug-2015
This global amendment includes:
-
Updates to Medical Monitor/Study Director
-
SCLC and Bladder: cohorts Nivo 3 mg/kg and Nivo 1/ Ipi 3 mg/kg, 
increase sample size.
-
Addition of Ovarian tumor type: cohorts Nivo 3 / Ipi 1 mg/kg and 
Nivo 1/ Ipi 3 mg/kg.
-
Updates to Blinded Independent Central Review (BICR) information
Allowing brain radiation prior to cross over
-
Allowing retreatment upon PD for patients with long lasting PR or 
CR and who had treatment held by investigator
-
For the combination arm, subjects who meet discontinuation criteria 
will be allowed to continue with nivolumab treatment should the 
study related toxicities be attributed to ipilimumab. Ipilimumab 
would be discontinued.
-
Updates to Primary, Secondary 
 Objectives
-
Updates to Discontinuation criteria to include Grade 4 
lymphocytopenia
Revised 
Protocol 03
07-Aug-2014
Incorporates Amendment 07 and 08
Amendment 08
07-Aug-2014
This amendment is to add nivolumab 3 mg/kg in combination with 
ipilimumab 1 mg/kg to the dose levels being investigated in study 
CA209-032, change the bladder cohort to a One Stage Design, and to add 
an optional external evaluation of CT or MRI scans for tumor types 
where data from study CA209-032 will potentially be used for future 
NDA submissions. Other changes were made to resolve minor 
inconsistencies and clarifications.
Amendment 07
04-Jun-2014
Pharmacogenetics blood sample update to include all current and future 
tumor types
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Clinical Protocol
CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Revised Protocol No.: 07d
Date: 03-Oct-2019
6
Document
Date of Issue
Summary of Change
Revised 
Protocol 02
17-Apr-2014
Incorporates Amendment 06
Amendment 06
17-Apr-2014
This global amendment includes adjustments to the treatment guidelines 
for patients with endocrinopathy events, adds a new cohort for subjects 
with Bladder Cancer, updates laboratory test requirements, and updates 
the sample size determination, populations for analyses and interim 
analysis sections. Other changes were made to resolve minor 
inconsistencies and clarifications:
• Bladder cancer is the most common malignancy of the urinary tract. 
Immunotherapy with Bacillus Calmette-Guerin in patients with 
superficial urothelial carcinoma is part of the standard treatment. It has 
been shown that CD8 tumor-infiltrating lymphocytes (TILs) are 
predictive of survival in muscle-invasive urothelial carcinoma. Active 
immunotherapeutic strategies have been investigated for bladder 
cancer including CTLA-4 blockade. In conclusion, a check point 
inhibitor therapy with nivolumab or nivolumab in combination with 
ipilimumab appears to be a promising experimental approach for 
patients with advanced urothelial carcinoma. This amendment adds a 
cohort enrolling subjects with advanced bladder cancer to the protocol 
aligned with the existing study design.
• Adjustments to the treatment guidelines for subjects who experience
endocrinopathy events are implemented. Subjects who experience 
endocrinopathy events which resolve or are adequately controlled with 
physiologic hormone replacement (steroids, thyroid hormones) or 
glucose controlling agents, may undergo retreatment. A recurrence of 
the endocrinopathy event under ongoing physiologic hormone 
replacement therapy appears to be unlikely what justifies a retreatment 
with potential therapeutic benefit.
• The definition of the all immunogenicity population was changed in 
order to align it with the core safety SAP for the Nivolumab program. 
Other minor changes in the populations for analyses were made in 
order to align it with the SAP for 032.
• The interim analysis section was updated to allow for IAs based on 
either a “super” response or if it is necessary to make decisions 
regarding further development (eg, the SCLC cohort).
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Clinical Protocol
CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
OVERALL RATIONALE FOR REVISED PROTOCOL 07D
This revised protocol provides clarity on the tumor assessments during treatment and follow-up. 
Additional changes were made for prohibited and restricted treatments. The changes apply for all 
participants in the study.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 07D
Section Number & 
Title
Description of Change
Brief Rationale
Section 3.4.1 Prohibited 
and/or Restricted Treatments
Section 3.4.2.3 Permitted 
Therapy
Updated language for permitted therapy and additional 
prohibited and/or restricted treatments were added: 

Any complementary medications (eg, herbal 
supplements or traditional Chinese medicines) 
intended to treat the disease under study. Such 
medications are allowed if they are used as 
supportive care.  

Any live / attenuated vaccine (eg varicella, zoster, 
yellow fever, rotavirus, oral polio and measles, 
mumps, rubella (MMR)) during treatment and 
until 100 days post last dose.
Prohibited and/or 
restricted treatments
were updated to align 
with program 
standards for safety.
Section 5 Study Assessments 
and Procedures
On-study Assessment tables:
Table 5.1-2
Table 5.1-3
Table 5.1-4
Table 5.1-5
Section 5.3.1 Imaging 
Assessment for the Study
Tumor assessment language was added to tables:
Additionally, with the exception of crossover 
participants, tumor assessments will not be required 
upon initiation of subsequent anti-cancer therapy.
On-treatment tables 
were updated to 
provide clarity that 
tumor assessments are 
not required after 
subjects receive 
subsequent anti-cancer 
therapy.  
Appendix 2
Management Algorithms were updated to include AE 
management for myocarditis
Appendix aligns with 
revised Nivolumab IB 
for safety.
Revised Protocol No.: 07d
Date: 03-Oct-2019
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Clinical Protocol
CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
SYNOPSIS
Clinical Protocol CA209032
Protocol Title: A Phase 1/2, Open-label Study of Nivolumab Monotherapy or Nivolumab combined with 
Ipilimumab in Subjects with Advanced or Metastatic Solid Tumors
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s):

Nivolumab monotherapy administered IV over 60 minutes at 3 mg/kg every 2 weeks until progression
or

Nivolumab administered IV over 60 minutes at 1 mg/kg combined with ipilimumab administered IV over 
90 minutes at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab administered IV over 60 minutes at 
3 mg/kg every 2 weeks until progression.
or

Nivolumab administered IV over 60 minutes at 1 mg/kg combined with ipilimumab administered IV over 
90 minutes at 3 mg/kg every 3 weeks for 4 doses followed by nivolumab administered IV over 60 minutes at 
3 mg/kg every 2 weeks until progression.
or

Nivolumab administered IV over 60 minutes at 3 mg/kg combined with ipilimumab administered IV over 
90 minutes at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab administered IV over 60 minutes at 
3 mg/kg every 2 weeks until progression.
or

Nivolumab administered IV over 60 minutes at 3 mg/kg every 2 weeks combined with ipilimumab administered 
IV over 90 minutes at 1 mg/kg every 6 weeks until progression.
or

Nivolumab administered IV over 30 minutes at 3 mg/kg every 2 weeks combined with ipilimumab administered 
IV over 30 minutes at 1 mg/kg every 6 weeks and cobimetinib 60 mg po qd 21 days on/7 days off until 
progression in patients with pancreatic cancer.
Study Phase: 1/2
Research Hypothesis: Treatment with nivolumab monotherapy, nivolumab combined with ipilimumab, or 
nivolumab combined with ipilimumab and cobimetinib will have clinical activity in subjects with advanced or 
metastatic tumors.
Objectives:
Primary Objective
SCLC Expansion Cohort:

To compare the objective response rate (ORR) as assessed by a Blinded Independent Central Review 
(BICR) for nivolumab monotherapy versus nivolumab combined with ipilimumab (nivolumab 1 mg/kg + 
ipilimumab 3 mg/kg)
Other Cohorts:

To evaluate the objective response rate (ORR) of nivolumab monotherapy, nivolumab combined with 
ipilimumab in subjects with advanced or metastatic tumors, or nivolumab combined with ipilimumab and 
cobimetinib in subjects from the additional pancreatic cancer cohort only. ORR will be assessed by the 
BICR in selected tumor types.
Revised Protocol No.: 07d
Date: 03-Oct-2019
9
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Clinical Protocol
CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Treatment assignment: The assignment to treatment arm and evaluation of safety and activity will be performed 
independently for each tumor type. For each tumor type, subjects will be assigned to one of the following treatment 
arms: 
Arm N: 
Nivolumab monotherapy (3 mg/kg) Q2W
Arm N-I Dose Level 1:
Nivolumab (1 mg/kg) + ipilimumab (1 mg/kg) Q3W for 4 doses, then nivolumab 
(3 mg/kg) Q2W
Arm N-I Dose Level 2: 
Nivolumab (1 mg/kg) + ipilimumab (3 mg/kg) Q3W for 4 doses, then nivolumab 
(3 mg/kg) Q2W
Arm N-I Dose Level 2b: Nivolumab (3 mg/kg) + ipilimumab (1 mg/kg) Q3W for 4 doses, then nivolumab 
(3 mg/kg) Q2W
Arm N-I Dose Level 2c: Nivolumab (3 mg/kg) Q2W + ipilimumab (1 mg/kg) Q6W
Arm N-I Dose Level 2d: Nivolumab 3 mg/kg Q2W + ipilimumab (1 mg/kg) Q6W + cobimetinib 60 mg po qd 
21 days on/7 days off for pancreatic cancer only
Revised Protocol No.: 07d
Date: 03-Oct-2019
11
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Clinical Protocol
CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Dose-escalating Safety Evaluation Phase for Combination Arm: Although the regimen currently used in the 
phase 3 melanoma study, nivolumab 1 mg/kg IV + ipilimumab 3 mg/kg, was expected to also be tolerable in the 
tumors studied here, an initial dose-escalating safety evaluation for the combination arms was conducted with GC, 
PC, TNBC, or SCLC (described in protocol Section 3.1.3). The BC cohort was added to this protocol following the
completion of the safety evaluations in GC, PC, TNBC, and SCLC at dose level 1 (nivolumab 1 mg/kg, ipilimumab 
1 mg/kg) which did not reveal safety concerns. Thereby the starting dose level for the BC cohort was dose level 2 
(nivolumab 1 mg/kg, ipilimumab 3 mg/kg). Six BC patients were initially randomized to Dose Level 2, after which 
enrollment to Dose Level 2b (nivolumab 3 mg/kg, ipilimumab 1 mg/kg) began.
Enrollment to Stage 1 for Arm N occurred in parallel to the safety evaluation for Arm N-I.
Two Stage Design: GC, PC, TNBC, or SCLC Arms N and N-I will follow a two-stage design to test whether 
nivolumab monotherapy or nivolumab combined with ipilimumab yields an objective response rate (ORR) that is of 
clinical interest in the investigated tumor types. For each tumor type, only treatment arms which meet an 
ORR threshold will proceed from Stage 1 to Stage 2 (described in protocol Section 3.1.4). Enrollment to Stage 2 in a 
given treatment arm can continue even if the other treatment arm is still in Stage 1.
Table 1:
Efficacy criteria to proceed from Stage 1 to Stage 2
Efficacy criteria
Next Step
2 or more of 18 subjects in a given arm have confirmed PR or CR
Go into Stage 2
1 or no of 18 subjects in a given arm have confirmed PR or CR.
No Go into Stage 2
For Stage 2, upon completion of enrollment of the initial 40 subjects, additional subjects may be assigned into 
Arm N and Arm N-I up to a total of 100 subjects (including those assigned in Stage 1) in each treatment arm of the 
given tumor type. For tumor types where nivolumab monotherapy or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg 
proceeded to Stage 2, assessment of Dose Level 2b in Stage 2 (nivolumab 3 mg/kg + ipilimumab 1 mg/kg, n=up to 
70 subjects) may be initiated for that tumor type. For SCLC, an additional 250 subjects (second- or third-line) will 
be randomized in a 3:2 ratio to one of the 2 expansion groups: nivolumab 3 mg/kg every 2 weeks or nivolumab 
1 mg/kg + ipilimumab 3 mg/kg every 3 weeks for 4 cycles followed by nivolumab 3 mg/kg.
Modified Design for Bladder Cancer Cohort:
Bladder arms N and N-I (Dose Levels 2 and 2b) will be conducted as a One Stage Design with the treatment of 
26-105 subjects in each arm. The Safety Evaluation Phase for the N-I arm will start at Dose Level 2 (nivolumab 
1 mg/kg, ipilimumab 3 mg/kg) and will evaluate safety and tolerability after the first 6 randomized subjects. 
Following the N-I safety evaluation phase, Dose Level 2 will treat approximately 92 subjects and 2b will treat up to 
a total of 105 subjects. Based on the safety evaluations thus far on study, no dose escalation phase is necessary for 
bladder cohort N-I Dose Level 2b (nivolumab 3 mg/kg, ipilimumab 1 mg/kg).
Modified Design for Ovarian Cancer Cohort:
Ovarian arm N-I (Dose Levels 2, 2b and 2c) will be conducted as a One Stage Design with the treatment of 
40 subjects in each arm. Due to the low risk of development of new safety signals on the combination arms no safety 
evaluation phase will be employed. Ovarian cancer subjects will be followed for related toxicities and decisions to 
stop treatment will be made on an ongoing basis.
Design for Additional Pancreatic Cancer Cohort:
Enrollment in the additional pancreatic cancer cohort will be initiated for one dose level N-I in combination with 
cobimetinib (Dose Level 2d) and will be conducted as a One Stage Design with the treatment of approximately 
30 subjects in one arm. Given that the toxicity profile of the combination of nivolumab and ipilimumab is 
well-characterized and cobimetinib has demonstrated a tolerable profile when combined with an similar agent in the 
PD-1/PD-L1 pathway, as well as that cobimetinib does not have overlapping toxicity profiles with nivolumab or 
ipilimumab, the combination of these 3 agents is not expected to increase frequency and/or severity of drug 
associated toxicities. Pancreatic cancer subjects will be followed for related toxicities and decisions to stop treatment 
will be made on an ongoing basis.
Revised Protocol No.: 07d
Date: 03-Oct-2019
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Clinical Protocol
CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Safety of the triplet combination in the proposed indication will be monitored continuously on a daily basis by the 
Medical Monitor, and enrollment will be staggered given the timing of amendment approval differ at individual sites 
as well as the limited number of eligible patients available at each site. No more than 6 patients will be enrolled in 
the first week of the study with subsequent enrollment of ≤ 6 subjects per week during the first month. A scheduled 
safety review by the Medical Monitor will occur after 12 patients are treated and have been followed for at least 1 
month and regular safety telephone conferences will be performed with the investigators participating in studying 
the triplet combination in the proposed indication.
SCLC expansion:
SCLC cohorts Arm N and Arm N-I met the pre-specified safety and efficacy criteria and proceeded to Stage 2. 
Based on an interim data review, disease control rates (SD + PR + CR) of 36% and 57% for Arms N and N-I, 
respectively, were estimated. In order to further investigate nivolumab and nivolumab combined with ipilimumab 
activity in specific SCLC subpopulations, the SCLC expansion cohorts will enroll additional subjects based on 
response to prior treatment and the number of previous therapies. Up to 250 second or third line subjects will be 
randomized in a 3:2 ratio to one of 2 expansion groups: Arm A (150 subjects treated with nivolumab 3 mg/kg every 
2 weeks (Q2W)) or Arm B (100 subjects treated with nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks 
(Q3W) for 4 cycles followed by nivolumab 3 mg/kg (Q2W) and will be stratified for number of prior treatment lines 
(1 vs 2 prior chemotherapy regimens). The crossover option refers only to the original cohorts and not the new 
cohorts enrolled under or after Amendment 09 implementation.
Crossover for subjects in Arm N: Subjects in Arm N may crossover to Arm N-I if all of the following criteria are 
met:

The Safety Evaluation Phase for the N-I regimen has been completed and at least 6 subjects have been exposed 
to the dose level used for Stage 1 of the N-I regimen. In case Dose Level 2b has been activated and the safety 
assessment completed, subjects for cross over will be assigned to Dose Level 2b.

Subject has confirmed radiologic disease progression (investigator-assessed RECIST 1.1 defined progression 
confirmed at least 4 weeks after the initial tumor assessment showing progression) in the absence of clinical 
deterioration. For subjects with clear evidence of new or progressing brain metastases a confirmation is not 
required. These subjects may proceed with brain radiation therapy and after having completed the radiation 
therapy a cross over to Arm N-I can be considered.

Subjects with rapidly progressing tumors under nivolumab monotherapy may undergo radiation treatment first 
before initiation of the cross over after discussion between the sponsor and investigator.

Subject has not experienced nivolumab related adverse events leading to permanent discontinuation.

Subject is not continuing to derive any clinical benefit from nivolumab single agent therapy as assessed by the 
investigator which would allow continuation of nivolumab monotherapy.

Subject is not a SCLC patient enrolled based on the Amendment 09 expansion.

The individual case must be discussed with the medical monitor prior to cross over.
Subjects crossing over to Arm N-I will start treatment at Day 1 Week 1 as described for subjects originally 
randomized to Arm N-I. Subjects who cross over and subsequently have an objective response in Arm N-I will not 
be considered in the decision making for Arm N I proceeding to Stage 2.
Study Population:
Key Inclusion Criteria

Subjects with histologically confirmed locally advanced or metastatic disease of one of the following tumor 
types and who meet the eligibility criteria:
o
Triple Negative Breast Cancer
o
Gastric Cancer
o
Pancreatic Cancer
o
Small Cell Lung Cancer
Revised Protocol No.: 07d
Date: 03-Oct-2019
14
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Clinical Protocol
CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
o
Bladder Cancer
o
Ovarian Cancer

Subjects must have measurable disease by CT or MRI per RECIST 1.1 criteria (radiographic tumor assessment 
must be performed within 28 days prior to first dose)

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Key Exclusion Criteria

Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if these have 
been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks 
after treatment is complete and within 28 days prior to first dose of study drug administration. There must also 
be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone 
equivalents) for at least 2 weeks prior to study drug administration.

Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, 
residual hypothyroidism due to autoimmune condition only requiring hormone replacement, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll.

Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone 
equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or 
topical steroids, and adrenal replacement doses are permitted in the absence of active autoimmune disease.

Prior therapy with experimental anti-tumor vaccines; any T cell co-stimulation or checkpoint pathways, such as 
anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, including ipilimumab; or other 
medicines specifically targeting T cell is also prohibited.
Study Assessments:
Tumor assessments
The primary endpoint of this study, ORR, is based on tumor assessments at baseline and then at 6 weeks from first 
dose. Tumor assessments continue every 6 weeks for the first 24 weeks and every 12 weeks thereafter while on 
treatment or on treatment hold for any reason until disease progression (investigator-assessed RECIST 1.1-defined 
progression) or treatment discontinuation, except for subjects treated beyond progression or who discontinued 
treatment for other reasons than PD.
Statistical Considerations:
Sample Size Determination
Sample size determination in the original protocol
This study comprises a Dose Escalating Safety Evaluation Phase for the Combination Arm, followed by a Staged 
Enrollment for Arm N, and Arm N-I. 
In the original protocol, gastric cancer, small cell lung cancer, triple negative breast cancer, and pancreatic cancer 
are included and the Staged Enrollment Part utilizes a modified Simon two-stage design with the treatment of 
40 subjects to evaluate whether nivolumab, or the combination of nivolumab/ipilimumab yields an objective 
response rate (ORR) that is of clinical interest. In this study, an ORR of 10% or less is considered not of clinical 
value, and an ORR of 25% or greater is considered of strong clinical interest. The modified Simon design evaluates 
the null hypothesis that the true response rate is 10% versus the alternative hypothesis that the true response rate is 
> 10%. The 2-stage testing within each cohort targets a Type I error rate of 5% and has 80% power to reject the null 
hypothesis if the true response rate is 25%.
Sample size determination for bladder cancer cohort
In Amendment 06, the bladder cohort is added. A one stage design with the treatment of 60-100 subjects is used for 
nivolumab monotherapy and the dose level 2b. These sample sizes will provide 90% to 97% power to reject the null 
hypothesis of 10% response rate if the true response rate is 25% with a two-sided Type I error rate of 5%.
Revised Protocol No.: 07d
Date: 03-Oct-2019
15
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Clinical Protocol
CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
In Amendment 14, the dose level 2 arm (nivolumab 1 mg/kg + ipilimumab 3 mg/kg) of the bladder cancer cohort is 
to enroll and treat a total of 92 subjects. A one stage design will be used. Based on a 19.6% ORR for nivolumab 
monotherapy (CA209275), the sample size of 92 in this arm will provide 93% power to reject the null hypothesis of 
19.6% response rate if the true response rate is 35% with a two-sided Type I error rate of 5%.
Sample size determination for SCLC expansion cohort
In Amendment 09, in addition to the original two-stage design of SCLC subjects, additional SCLC expansion cohort 
subjects will be randomized in a 3:2 ratio to one of 2 expansion groups: Arm A (150 subjects, nivolumab mono) or 
Arm B (100 subjects, nivolumab 1 mg/kg + ipilimumab 3 mg/kg) and will be stratified for number of prior treatment 
lines (1 vs 2 prior chemotherapy regimens). 
Based on SCLC data so far observed in this study with an ORR of about 10% for nivolumab monotherapy and about 
23% for nivolumab / ipilimumab combination therapy, sample sizes of N = 150 for nivolumab monotherapy and 
N = 100 for nivolumab / ipilimumab combination therapy (nivolumab 1 mg/kg + ipilimumab 3 mg/kg) will target a 
Type I error rate of 5% (two-sided) and will have 78% power to detect the difference between these two arms, if the 
true ORR rates are 10% and 23%, respectively.
Sample size determination for ovarian cancer cohort
Also in Amendment 09, an ovarian cancer cohort is added and a one stage design with the treatment of 40 subjects 
for each arm is used. These sample sizes provide 79% power to reject the null hypothesis of 10% response rate if the 
true response rate is 25% with a two-sided Type I error rate of 5%.
Sample size determination for the additional pancreatic cancer cohort
In this Amendment, pancreatic cancer cohort is re-opened and one stage design with the treatment of 30 subjects 
will be used. This sample size will provide 70% power to reject the null hypothesis of 10% response rate if the true 
response rate is 25% with a two-sided Type I error rate of 5%.
Primary Endpoint:
Objective Response Rate
Analyses:
ORR will be summarized for each cohort by a binomial response rate and corresponding two-sided 95% exact CI 
using the method proposed by Atkinson and Brown for cohorts using a two-stage design and the Clopper-Pearson 
method for cohorts using a one stage design.
For SCLC expansion cohort, the estimated difference including 95% CI of the estimated difference along with its 
corresponding p-value of ORR assessed by BICR between nivolumab monotherapy and nivolumab/ipilimumab 
combination therapy (nivolumab 1 mg/kg + ipilimumab 3 mg/kg) will be presented with 95% CI. Similar methods 
will be used to summarize ORR for each stratification factor. However, the p-value will not be provided for each 
stratification factor.
DOR as determined by the investigator or BICR for selected tumor types will be summarized for subjects who 
achieve confirmed PR or CR using the Kaplan-Meier (KM) product-limit method. Median values of DOR, along 
with two-sided 95% CI using the Brookmeyer and Crowley method will also be calculated by cohort. In addition, 
the percentage of responders still in response at different time points (3, 6, and 12 months) will be presented based 
on the KM plot.
The magnitude of reduction in tumor burden will be summarized descriptively.
Secondary Endpoints:
Safety will be assessed on all treated subjects. The rate of treatment-related adverse events leading to drug 
discontinuation within the first 12 weeks of treatment will be assessed.
PFS is defined as the time from treatment assignment in IVRS to the date of the first documented tumor progression 
or death due to any cause, whichever occurs first. 
OS is defined as the time between the date of treatment assignment in IVRS and the date of death due to any cause. 
A subject who has not died will be censored at the last known alive date.
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Analysis:
Treatment-related AEs leading to discontinuation will be tabulated using worst grade per NCI CTCAE v 4.0 criteria 
by system organ class and preferred term. All on-study AEs, Grade 3-4 AEs, treatment-related AEs, Grade 3 4 
treatment-related AEs, SAEs, treatment-related SAEs, and AEs leading to discontinuation will be tabulated using 
worst grade per NCI CTCAE v 4.0 criteria by system organ class and preferred term. On-study lab parameters 
including hematology, chemistry, liver function, and renal function and Grade 3-4 Lab Abnormalities will be 
summarized using worst grade NCI CTCAE v 4.0 criteria.
PFS and OS will be summarized descriptively using Kaplan-Meier methodology. Median values of PFS and OS, 
along with two-sided 95% CIs using the Brookmeyer and Crowley method, will be calculated for each cohort. PFS 
rates at 6 and 12 months, and OS rates at 12 and 24 months will also be estimated. Associated two-sided 95% CIs 
will be calculated using the Greenwood formula. Additional survival analysis may be conducted for up to 5 years 
beyond analysis of the primary endpoint.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR REVISED PROTOCOL 07D ................................... 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 07D ...................... 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.1.1 Rationale for Investigating Unresectable Locally Advanced or Metastatic 
Triple Negative Breast Cancer (TNBC) ...................................................... 
1.1.2 Rationale for Investigating Unresectable Locally Advanced or Metastatic 
Limited or Extensive Stage Small Cell Lung Cancer (SCLC)..................... 
1.1.3 Rationale for Investigating Unresectable Locally Advanced or Metastatic 
Gastric and Gastro-Esophageal-Junction Cancer (GC) ............................ 
1.1.4 Rationale for Investigating Unresectable Locally Advanced or Metastatic 
Pancreatic Adenocarcinoma Cancer (PC) ................................................. 
1.1.5 Rationale for Investigating Unresectable Locally Advanced or Metastatic 
Bladder Cancer (BC) .................................................................................. 
1.1.6 Rationale for Investigating Unresectable Locally Advanced or Metastatic 
Ovarian Cancer (OC) ................................................................................. 
1.1.7 Rationale for Investigating Nivolumab Combined with Ipilimumab and 
Cobimetinib in Pancreatic Cancer ............................................................. 
1.1.8 Summary of Results from the Ipilimumab and Nivolumab Programs ..... 
1.1.8.1 Preclinical Summary of Nivolumab Combined with Ipilimumab ... 
1.1.8.2 Summary of Safety ........................................................................... 
1.1.8.3 Summary of Clinical Activity .......................................................... 
1.1.9 Rationale to Support Dose/Schedule of Nivolumab Combined with 
Ipilimumab .................................................................................................. 
1.1.10 Rationale for Shorter Nivolumab and Ipilimumab Infusion Times in 
Additional Pancreatic Cancer Cohort ........................................................ 
1.1.11 Rationale for Permitting Continued Treatment in Select Cases of 
Progressive Disease .................................................................................... 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objective .................................................................................... 
1.3.2 Secondary Objective ................................................................................ 
 
1.4 Product Development Background ................................................................... 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
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5.8 Other Assessments ............................................................................................ 
5.8.1 Immunogenicity Assessments ................................................................... 
5.8.2 Pharmacogenetic Research ..................................................................... 
5.8.3 Demographics and Medical History ........................................................ 
5.9 Blinded Independent Central Review (BICR) .................................................. 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
6.8 Safety Assessments ........................................................................................... 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 Primary Endpoint Methods ............................................................. 
8.4.2.2 Secondary Endpoint Methods ......................................................... 
 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.5 Biomarker Analyses ................................................................................. 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.7 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
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9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 PERFORMANCE STATUS SCALES ................................................. 
APPENDIX 2 MANAGEMENT ALGORITHMS ....................................................... 
APPENDIX 3 RECIST 1.1 ........................................................................................... 
APPENDIX 4 DEFINITION OF PRIOR RESPONSE TO PLATINUM-BASED 
CHEMOTHERAPY IN SCLC ............................................................................... 
APPENDIX 5 DEFINITION OF PRIOR RESPONSE TO PLATINUM-BASED 
CHEMOTHERAPY IN OVARIAN CANCER ...................................................... 
APPENDIX 6 ROYAL MARSDEN PROGNOSTIC SCORE .................................... 
APPENDIX 7 METHODS OF CONTRACEPTION ................................................... 
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1
INTRODUCTION AND STUDY RATIONALE
Nivolumab (BMS-936558; anti-PD-1 mAb) is a fully human monoclonal immunoglobulin (Ig) 
G4 antibody that binds to the programmed death-1 (PD-1) cell surface membrane receptor, a 
negative regulatory molecule expressed by activated T and B lymphocytes. Inhibition of the 
interaction between PD-1 and its ligands promotes immune responses and antigen-specific T cell 
responses to both foreign antigens as well as self antigens. PD-1 receptor blockade by nivolumab 
is a new approach for immunotherapy of tumors. Results from a Phase 1/2 study (CA209003)1
indicate that nivolumab is active in multiple tumor types. Nivolumab 3 mg/kg monotherapy is 
currently approved for the treatment of advanced melanoma and non-small-cell lung cancer, 
metastatic renal carcinoma, and Hodgkin lymphoma, and is being studied in several Phase 3 and 
2 clinical trials in advanced and metastatic solid and hematologic malignancies.
Ipilimumab is a fully humanized IgG1 monoclonal antibody binding to the anti-cytotoxic T-cell 
lymphoma-4 antigen (CTLA-4). Ipilimumab is an approved therapy for metastatic melanoma 
[YervoyPrescribing Information, 2011] and has demonstrated improved overall survival as 
monotherapy and in combination with dacarbazine.2,3 Ipilimumab has been studied in 
combination with multiple standard of care (SOC) therapies including chemotherapy for 
squamous and non-squamous NSCLC and radiotherapy for hormone resistant prostate cancer.4
Ipilimumab is currently also approved as adjuvant therapy in stage III melanoma.
Preclinical and clinical data indicate that the combination of PD-1 and CTLA-4 receptor
blockade may improve antitumor activity. In vitro combinations of nivolumab plus ipilimumab 
increase IFN-production 2- to 7-fold over either agent alone in a mixed lymphocyte reaction. In 
a murine melanoma vaccine model, blockade with either CTLA-4 or PD-1 antibodies increased 
the proportion of CTLA-4 and PD-1-expressing CD4/CD8 tumor infiltrating T effector cells, and 
dual blockade increased tumor infiltration of T effector cells and decreased intratumoral 
T regulatory cells, as compared to either agent alone.5
In the Phase 1 dose escalation study CA209004, the combination of nivolumab and ipilimumab 
has been studied in subjects with unresectable or metastatic melanoma. In this study, a safe dose 
level for the combination of ipilimumab and nivolumab was established for the treatment of 
advanced melanoma. At this dose level, 1 mg/kg nivolumab plus 3 mg/kg ipilimumab, an 
objective response rate of 53% was observed. This regimen was studied in a global, randomized 
Phase 3 study in advanced melanoma, CA209067.6 Based on the results of the CA209067 study, 
the combination therapy of 1 mg/kg nivolumab plus 3 mg/kg ipilimumab is approved for the 
treatment of patients with unresectable or metastatic melanoma regardless of BRAF mutational 
status.
The combination of nivolumab with ipilimumab has been investigated in NSCLC (study 
CA209012)7, metastatic clear cell renal cell carcinoma (mRCC) (study CA2090168). Data from 
these Phase 1/2 studies show, that the dose level of 3 mg/kg nivolumab plus 1 mg/kg ipilimumab 
is well tolerated while preserving the tumor efficacy.9,10
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Based on the promising results in study CA209004, study CA209032 is designed as a signal 
detection study for safety and efficacy in a variety of tumor types investigating nivolumab as a 
single agent or in combination with ipilimumab.
Pancreatic cancer is included in the tumor types that have been evaluated in CA209032. The 
combination of nivolumab and ipilimumab has been shown to be more effective than either agent 
in monotherapy in the treatment of a variety of tumors including melanoma, lung, and renal cell 
carcinoma.6,7,8 Given the mechanism of anti-tumor activity of immuno-oncology agents is 
indirect and functions through the host immune system, there is good rationale that nivolumab 
and ipilimumab would be effective in pancreatic cancer. However, there was modest activity 
observed for nivolumab and nivolumab combined with ipilimumab in this indication. This lack 
of response to immune therapies may be related to the KRAS/MEK pathway. Recent published 
data have suggested that KRAS mutant tumors may be predisposed to combined therapy with a 
mitogen/extracellular signal regulating kinase (MEK) and agents targeting PD-1 and CTLA-4 
pathways.11 Therefore, the cohort aims to continue investigating the original hypothesis of 
whether nivolumab and ipilimumab can treat pancreatic cancer, but leveraging additional 
pathways which may enhance the ability for a clinically effective anti-tumor immune response.
1.1
Study Rationale
Study CA209032 is an open label multi-center Phase 1/2 study to investigate the safety and 
efficacy of nivolumab monotherapy or nivolumab and ipilimumab in combination in 6 tumor
types - triple-negative breast cancer (TNBC), gastric cancer (GC), pancreatic adenocarcinoma 
(PC), small cell lung cancer (SCLC), bladder cancer (BC) and ovarian cancer (OC).
1.1.1
Rationale for Investigating Unresectable Locally Advanced or 
Metastatic Triple Negative Breast Cancer (TNBC)
Breast cancer is classified by clinicopathological features based on the expression of hormone 
receptors for estrogen (ER) and progesterone (PR) as well as the human epidermal growth factor 
receptor 2 (HER2).12 Triple negative breast cancer is an aggressive disease characterized by the 
lack of ER/PR and HER2 expression. TNBC is mostly of the basal type and accounts for 
15 - 20% of cases of breast cancer.13,14 Most BRCA1 mutation associated tumors are basal type 
and triple-negative.15
While TNBC is not responsive to hormonal or HER2-targeted agents, these tumors are 
responsive to anthracycline/taxane based chemotherapy in the adjuvant and neo-adjuvant setting 
which may induce complete pathological response (pCR).16,17 However, the majority of TNBC 
patients have residual disease with high risk of relapse and rapid decrease in survival within the 
3 - 5 year post-treatment.18,19
There are no standard chemotherapy regimens for previously treated TNBC patients. Treatment 
with capecitabine, gemcitabine, vinorelbine or nab-paclitaxel -
either alone or in 
combination - has been used in second line therapy for metastatic breast cancer. Positive results 
for the subset of TNBC are obtained from the Phase 3 trials for ixabepilone approval in the USA 
and eribulin approval in the EMA for metastatic breast cancer prior-treated with anthracyclines 
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and taxanes. In the subset of TNBC patients from a 752 patient trial with anthracycline/taxane 
pre-treated breast cancer patients, improved PFS (4.2 vs 1.7 months for ixabepilone plus 
capecitabine compared to capecitabine alone, HR = 0.63, 95% CI 0.52-0.77, P < 0.0001) and 
ORR (27%) was observed.20 In the Phase 3 EMBRACE study (N = 762), of eribulin versus 
treatment of physician’s choice (TPC), eribulin demonstrated statistically significant OS increase 
(median OS 13 versus 11 months, HR = 0.81, P = 0.041).21 In TNBC patients, the experimental 
arm conferred a 29% decreased risk of death.22
Among other agents, platinum-based regimens and PARP inhibitors (olaparib, iniparib, BSI-201) 
have shown promising results in TNBC, particularly in association with BRCA-mutation in the
tumors. Vascular endothelial growth factor targeted therapy (bevacizumab, sunitinib, sorafenib) 
have also shown some activity.23 However, true estimation of benefit from large trials is still 
awaited.
Establishing a standard of care with significant benefit in metastatic TNBC with prior 
anthracycline/taxane failure is an urgent unmet need. Immunotherapy may provide a path 
forward. A meta-analysis of 996 patients receiving neoadjuvant chemotherapy indicated an 
association of response to high scores for immune modules assessed by gene expression 
analysis.24 In a preliminary BMS immuno-histochemistry survey of breast cancer tumor bank 
samples, TNBC has the highest percentage (18%) of samples positive for PD-L1 expression. 
Therefore, a monotherapy with a checkpoint inhibitor or the combination of check-point 
inhibitors like nivolumab may offer improved benefit for metastatic TNBC.
1.1.2
Rationale for Investigating Unresectable Locally Advanced or 
Metastatic Limited or Extensive Stage Small Cell Lung Cancer (SCLC)
SCLC accounts for 15 - 20% of new cases of lung cancer, and nearly 33,900 new cases are 
expected in the US in 2012. 25 SCLC is traditionally classified as Limited Stage Disease 
(LD-SCLC - tumor tissue encompassed within a single radiation port) and Extensive Stage 
Disease (ED-SCLC - tumor that extends beyond the boundaries of a single radiation port).26
For LD-SCLC, a combined therapeutic approach of radiotherapy, chemotherapy and rarely 
surgery is used with curative intent.27 Most patients at diagnosis have ED-SCLC and are treated 
with four to six cycles of platinum plus etoposide (PE) which remains the standard chemotherapy 
regimen for LD- and ED-SCLC. Initial response rate is robust with 70-90% response seen in 
LD-SCLC and 50 - 70% response seen in ED-SCLC.27 Whenever, overall survival remains poor 
with median survival for LD-SCLC at 18-30 months28 and for ED-LCSC in the range of 
10-12 months.29
Following platinum-based first line therapy, about 80% LD-LSC patients and all of ED-SCLC 
patients have disease progression.30 Patients whose response after first line platinum-based 
therapy last beyond 180 days are the best candidates for re-challenge with platinum-doublet 
therapy. Others are treated with single-agent topotecan - the only approved second-line therapy 
in the US. Approval was based on a Phase 3 study showing superiority of single-agent 
intravenous topotecan over a regimen consisting of cyclophosphamide, doxorubicin and 
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vincristine (CAV) with an improved ORR (24.3% vs 18.3%, p= 0.285) and mOS similar 
between two arms (25 weeks vs 24.7 weeks). 31
New treatments for SCLC are required. An analysis of peripheral blood mononuclear cells 
(PBMCs) from SCLC patients has shown that T-effector cells are more in LD-SCLC compared 
to ED-SCLC subjects and long-term survivors of SCLC have a higher T-effector to T-regulator 
ratio.32 In a Phase 2 randomized study, ipilimumab in combination with carboplatin and 
paclitaxel showed improved PFS versus carboplatin and paclitaxel (5.7 months vs 4.6 months, 
HR = 0.72, P = 0.05), though there was no improvement when used concurrently.33 Nivolumab 
at doses of 1, 3, and 10 mg/kg has been shown to be effective against NSCLC in a Phase 1 study 
(N = 122) with ORR of 6%, 27%, and 17% and PFS rates at 24 weeks of 25%, 44%, 
and 31%.34,35 Considering the immune response seen in SCLC patients, and the results of 
checkpoint inhibitors nivolumab and ipilimumab in NSCLC patients, it is reasonable to expect 
that nivolumab alone or in combination with ipilimumab is likely to provide benefit in 
second-line and further lines of treatment of SCLC.
1.1.3
Rationale for Investigating Unresectable Locally Advanced or 
Metastatic Gastric and Gastro-Esophageal-Junction Cancer (GC)
Globally, gastric cancer is the 4th leading cancer with over 900,000 diagnosed new cases and is 
the second leading cause of cancer-related death with 700,000 deaths reported annually. The 
geographic distribution is varied across the globe with the highest burden of disease seen in 
Eastern Europe, South America and Asia.36 Gastro-esophageal junction (GEJ) cancer 
anatomically straddles the distal esophagus and proximal stomach. Due to the location and since 
the majority of GEJ tumors are adenocarcinomas, these tumors are frequently grouped together 
with gastric cancer. Until optimal treatment strategies are defined, advanced and metastatic 
GEJ cancer is treated and managed in a similar fashion to gastric cancer.37,38
Gastric cancer often presents with advanced disease upon diagnosis (except in countries like 
Japan and Korea where early detection is common). In about 20-30% of cases, subjects will 
present with resectable disease but in many of these, intraoperative discovery of lymph node 
metastasis is common and where curative surgery is possible, the recurrence rate after resection 
is high. For subjects developing advanced and metastatic disease, the reported 1-year survival is 
approximately 30%.39 With first-line treatment, the median survival for these subjects is 
approximately 8 to 14 months and with best supportive care alone is approximately 3 months.
First-line chemotherapy generally consists of a fluroropyrimidine and or a platinum combination 
regimen.40 There is still no universal consensus on the standard or reference regimen resulting in 
regional and even institutional differences seen in the choice of backbone chemotherapy.41,42
Options for first-line therapy would include S1, 5FU or capecitabine for the fluroropyrimidine 
agent, and cisplatin or oxaliplatin for the platinum agent. Of note, no doublet combination of 
fluroropyrimidine plus platinum has been demonstrated to be superior to another in a 
Phase 3 randomized controlled trial in terms of efficacy although there are reported differences 
in the toxicity profiles between the regimens.43,44 Though the results of the V325 Phase 3 trial 
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showed that the addition of docetaxel to cisplatin and 5FU combination improved time to 
progression with a small improvement in median survival, this is at the expense of increased 
toxicity.45 As a consequence, docetaxel is limited to the first line treatment of gastric cancer.
Trastuzumab has been shown to have survival benefit in combination with chemotherapy for 
Her2 positive gastric cancer and improved median survival to 13.8 months.46 This treatment is 
only applicable to those who exhibit Her2 positive disease comprising 10 - 30% of all the gastric 
cancer population.47
For patients after failure of first line platinum-fluoropyrimidine based chemotherapy there is an 
urgent medical need to find new therapeutic approaches. In gastric cancer, CTLA-4 blockade has 
been reported to induce antitumor response. Tremelimumab, a fully humanized anti-CTLA4 
monoclonal antibody was assessed for its activity as second-line treatment for subjects with 
gastric cancer.48 In a Phase 2 trial tremelimumab was administered on a 3-monthly schedule to a 
small group (n = 18) of subjects. Although the objective response rate was noted to be only 5%, 
the median survival was 4.8 months similar to other reported second-line chemotherapies for 
gastric cancer. Therefore, a checkpoint inhibitor (nivolumab) alone or in combination with each 
other (nivolumab plus ipilimumab) may offer improved benefit for patients with locally 
advanced or metastatic Gastric and Gastro-Esophageal-Junction Cancer.
1.1.4
Rationale for Investigating Unresectable Locally Advanced or 
Metastatic Pancreatic Adenocarcinoma Cancer (PC)
Pancreatic adenocarcinoma is one of the deadliest forms of cancer with rising incidence during 
the past several decades. It is estimated that 45,200 new cases will be diagnosed and 
38,460 people will die of pancreatic carcinoma in the United States in 2013.49 The 1-year and 
5-year survival rates for newly diagnosed patients are 15% and < 5% respectively.50
Radical surgery in early stage disease (Stage I and some Stage II) maybe the only treatment with 
curative intent in pancreatic cancer.51 For locally advanced or metastatic disease (Stage IV), 
gemcitabine has been the standard of care with a median survival of 6.2 months and a 1 year 
survival rate of 20%.52 The Phase 3 PRODIGE trial [N = 342] comparing FOLFIRINOX 
(combination of 5-FU, leucovorin, irinotecan, oxaliplatin) to gemcitabine in metastatic 
pancreatic cancer patients of good performance status (PS 0 in 75 year olds) showed 
significant improvement in median PFS (6.4 months vs 3.3 months, P < 0.001) and 
median OS (11.1 months vs 6.8 months, p < 0.001) with FOLFIRINOX.53
No established standard of care exists for subjects who progress after first line therapy in the 
advanced or metastatic therapy. There is an urgent need to find better treatment for pancreatic 
cancer. The NCCN Guideline for the treatment of pancreatic cancer state that all subjects with 
pancreatic cancer - irrespective of their line of treatment - should be considered for clinical 
trials.54 Since nivolumab and ipilimumab act through a mechanism that is directed towards 
activating inactive T-cells, and has been shown to be active across multiple tumor types, it is 
reasonable to test the hypothesis that nivolumab alone or in combination with ipilimumab will 
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provide a response rate and depth of response (tumor shrinkage) that may translate to improved 
overall survival or provide quality of life benefits.
However, there was modest activity observed for nivolumab and nivolumab combined with 
ipilimumab in this indication on this clinical study. This lack of response to immune therapies 
may be related to the KRAS/MEK pathway. MEK inhibition alone in immunocompetent mice 
harboring a colon carcinoma cell line with mutant KRAS-G12D treated with the highly potent 
and specific MEK-inhibitor G-38963 (which is similar to cobimetinib) resulted in intratumoral 
CD8+ T cell accumulation and class I MHC upregulation.55 In additional experiments in 
preclinical models, MEK inhibition synergized with anti-PD1 to promote durable tumor 
regression while promoting the effector phenotype and longevity of tumor-infiltrating CD8+ 
T cells. Investigations conducted by Liu and coworkers showed that MEK inhibitors in 
combination with PD-1 and CTLA 4 receptor blockade exhibit synergistic antitumor activity in 
mouse models with increased tumor-infiltrating CD8+ T cells in CD26 tumors.11
The MEK pathway is a critical mediator of the constitutively active mutant form of KRAS, 
KRAS-G12D, in many tumors including colorectal cancer (CRC) and pancreatic cancer. The 
clinical activity and safety of cobimetinib, an MEK inhibitor, were recently reported in results of 
a Phase1/2 clinical study in patients with advanced and metastatic CRC with a median of 3 prior 
treatment lines.56 Cobimetinib when combined with an anti-PD-L1 antibody, azetolizumab, 
achieved an ORR of 17% in all treated CRC patients and 20% in patients with KRAS mutation; 
the 6-month OS rates were 72% and 77%, respectively. The most common adverse effects 
associated with this combination treatment were diarrhea, fatigue, and skin toxicities. 
Cobimetinib (Cotellic) is currently approved in combination with vemurafenib for the 
treatment of metastatic melanoma.57
In addition to CRC, pancreatic cancer is also associated with KRAS mutations, with the most 
common mutation being KRAS-G12D58, and the activation of several effector pathways 
downstream of KRAS, including MEK kinases MEK1/259. Hence, study CA209032 is adding a 
pancreatic cancer cohort to detect safety and efficacy signals in this tumor type investigating 
nivolumab in combination with ipilimumab and cobimetinib.
1.1.5
Rationale for Investigating Unresectable Locally Advanced or 
Metastatic Bladder Cancer (BC)
Bladder cancer is the most common malignancy of the urinary tract. Five percent (5%) of the 
patients have Stage IV disease at presentation.60 Immunotherapy with Bacillus Calmette-Guerin 
in patients with superficial urothelial carcinoma reduces the risk of local recurrence by 60% and 
can lead to 5-year survival rates of 90% in patients with unifocal.61 CD8 tumor-infiltrating 
lymphocytes (TILs) are predictive of survival in muscle-invasive urothelial carcinoma. Patients 
with advanced urothelial cancer (pT2, pT3, or pT4) and higher numbers of CD8 TILs within the 
tumor (> 8) had better disease-free survival (P < 0.001) and overall survival (P = 0.018) than did 
patients with similar-staged urothelial carcinoma and fewer intratumoral CD8 TILs.62
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Active immunotherapeutic strategies have been investigated for bladder cancer showing that 
immune and antitumor responses are induced.63 The safety of pre-operative CTLA-4 blockade in 
patients with bladder cancer has been demonstrated.64 The efficacy and safety of first-line 
gemcitabine, cisplatin + ipilimumab for metastatic urothelial carcinoma is currently being 
investigated in a Phase 2 trial (NCT01524991). Recently, inhibition of PD-L1 by MPDL3280A 
was shown to have clinical activity in patients with metastatic urothelial bladder cancer.65
Based on the study results, Tecentriq(atezolizumab, MPDL3280A) was granted approval for 
the treatment of patients with advanced urothelial carcinoma by the FDA. Nivolumab has also 
demonstrated meaningful antitumor activity in advanced urotheilal carcinoma66.
In conclusion, a check point inhibitor therapy with nivolumab alone or nivolumab in 
combination with ipilimumab appears to be a promising experimental approach for patients with 
advanced urothelial carcinoma.
1.1.6
Rationale for Investigating Unresectable Locally Advanced or 
Metastatic Ovarian Cancer (OC)
The term ovarian cancer includes not only epithelial ovarian cancer but also primary peritoneal 
and fallopian tube cancer. The latter two are less common neoplasms, which, however, are 
managed in a similar manner to epithelial ovarian cancer. Epithelial ovarian cancer is the leading 
cause of death from gynecologic cancer in the United States and is the country’s fifth most 
common cause of cancer mortality in women.67 Nearly 75 % of the patients present with 
advanced stage OC.68 According to the International Federation of Gynecology and Obstetrics 
(FIGO), 5-year survival rates are approximately 46.7% for Stage IIIa, 41.5% for Stage IIIb, 
32.5% for Stage IIIc, and 18.6% for Stage IV.69 Whereas patients with platinum-sensitive OC 
treated with platinum-based frontline therapy have a high response rates up to 81% and a mPFS 
and mOS of 19.1 and 44.1 months, respectively70, subjects with subsequent relapses, either 
platinum-sensitive or -resistant, have a significantly worse prognosis with a mPFS between 
10.2 and 4.1 months and a mOS between 17.6 and 5.0 months, respectively.71 Immunotherapy 
with weekly intraperitoneal IL-2 produced a ~ 17% complete pathologic response rate in patients 
with platinum-resistant OC.72 A threefold prolongation of PFS was observed in patients treated 
with rhIFN-combined with MTD cisplatin and cyclophosphamide chemotherapy, with minimal 
added toxicity.73,74 The presence of tumor-infiltrating lymphocytes (TILs) in advanced stage OC 
correlates with an improved outcome. Patients with Stage III and IV OC and the presence of 
TILs within the tumor (either grade) had better disease-free survival and overall survival 
(P < 0.001) than did patients with similar-staged ovarian cancer and absence of TILs.75
Therefore, use of immunotherapeutic agents in treatment of advanced OC is justified.
Indeed, active immunotherapeutic strategies with check point inhibitors have been investigated 
for ovarian cancer showing encouraging clinical activity signals with a good tolerability of 
nivolumab, PD-1 inhibitor.76 The efficacy and safety of ipilimumab 10 mg/kg monotherapy for 
recurrent ovarian cancer is currently being investigated in a Phase 2 trial.77 No new safety 
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signals have been identified in this clinical study, so far. Recently, inhibition of PD-1 by MK-
3475 has been shown to be well tolerated and have clinical activity in patients with PD-L1 
positive advanced ovarian cancer.78 In conclusion, a check point inhibitor therapy with 
nivolumab or nivolumab in combination with ipilimumab appears to be a promising 
experimental approach for patients with advanced ovarian carcinoma.
1.1.7
Rationale for Investigating Nivolumab Combined with Ipilimumab and 
Cobimetinib in Pancreatic Cancer
The combination of nivolumab and ipilimumab is more effective than either agent in 
monotherapy in the treatment of a variety of tumors including melanoma, lung, and renal cell 
carcinoma.6,7,8 Given the mechanism of anti-tumor activity of immuno-oncology agents is 
indirect and functions through the host immune system, there is good rationale that nivolumab 
and ipilimumab would be effective in pancreatic cancer. Nivolumab and ipilimumab have only 
had modest activity in the treatment of metastatic pancreatic cancer. Recent data in KRAS 
mutant tumors has suggested that MEK pathway inhibition can augment the effectiveness of PD-
1/PD-L1 pathway targeted therapies.79 Therefore, this cohort continues to interrogate the original 
hypothesis of whether nivolumab and ipilimumab can generate effective clinical activity in 
pancreatic cancer (a tumor with high prevalence of KRAS mutations) through the addition of a 
MEK inhibitor.
Cotellic(cobimetinib) is an orally bioavailable, potent, selective MEK inhibitor. Preclinical 
observations and initial results of a Phase 1b trial combining cobimetinib and anti-PD-1 agent 
atezolizumab in patients with KRAS-mutant metastatic CRC indicate that metastatic cancer can 
be sensitized for immunotherapy by inhibition of MEK-dependent intracellular signaling.56 It is 
expected that the combination of nivolumab with ipilimumab and cobimetinib will have a 
synergistic effect in pancreatic cancer without overlapping toxicities.
The most common toxic events associated with single-agent use of cobimetinib in Phase 1 
testing were diarrhea, rash, fatigue, and edema; Grade 3 or higher events included diarrhea, rash, 
and fatigue.80
Drug-drug interactions between nivolumab/ipilimumab and cobimetinib are not expected. It is 
not likely that other drugs will affect the PK of nivolumab or ipilimumab because nivolumab is 
an IgG4 monoclonal antibody, and ipilimumab is an IgG1 monoclonal antibody, which are 
eliminated by non-specific catabolism (often by reticuloendothelial system proteases). This 
elimination process is not known to be inhibited or induced by small molecule drugs. Nivolumab 
is also unlikely to impact the PK of other companion drugs when used in combination regimens. 
A Phase 1 study in metastatic clear cell renal cell carcinoma (CA209009) demonstrated that 
nivolumab at all dose levels (0.3, 2, and 10 mg/kg) did not modulate cytokine levels (IL6, IL2, 
and IL10). Because no change in cytokine level was observed, nivolumab is not considered to 
mediate CYP induction, and has no or low potential for modulating CYP enzymes, and thereby a 
low risk of interaction with small molecule drugs. Similarly, ipilimumab is not expected to have 
drug-drug interaction with cobimetinib because ipilimumab, as a monoclonal antibody is 
unlikely to have an effect on CYPs or other drug-metabolizing enzymes.
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The pancreatic cancer cohort will enroll subjects to a combination of Nivolumab administered IV 
at 3 mg/kg every 2 weeks combined with ipilimumab administered IV at 1 mg/kg every 6 weeks 
with cobimetinib 60 mg po qd 21 days on/7 days off.
The dose level of cobimetinib used in this clinical study is based on the dose approved for the 
combination of cobimetinib with vemurafenib for the treatment of patients with unresectable or 
metastatic melanoma with a BRAF V600E or V600K mutation.57 This dose was also used in the 
Phase I clinical study of cobimetinib combined with 800 mg atezolizumab conducted by 
Bendell.56 In this study, the dose of 60 mg of cobimetinib per os daily in combination with a PD-
L1 antibody was safe and well tolerated.
1.1.8
Summary of Results from the Ipilimumab and Nivolumab Programs
1.1.8.1
Preclinical Summary of Nivolumab Combined with Ipilimumab
Preclinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may 
improve antitumor activity. In vitro combinations of nivolumab plus ipilimumab increase 
IFN-production 2- to 7-fold over either agent alone in a mixed lymphocyte reaction. Increased 
antitumor activity of the combination was also observed in 3 of 5 syngeneic murine cancer 
models. In a murine melanoma vaccine model, blockade with either CTLA-4 or PD-1 antibodies 
increased the proportion of CTLA-4 and PD-1-expressing CD4/CD8 tumor infiltrating T effector 
cells, and dual blockade increased tumor infiltration of T effector cells and decreased 
intratumoral T regulatory cells, as compared to either agent alone.81
In a 4-week toxicity study of nivolumab in combination with ipilimumab conducted in 
cynomolgus monkeys demonstrated that the combination of nivolumab and ipilimumab resulted 
in dose-dependent gastrointestinal (GI) toxicity. Histologic findings included inflammatory 
changes in the large intestine, which increased in incidence and severity in a dose-dependent 
manner. GI toxicity/colitis was not observed in cynomolgus monkeys administered nivolumab 
alone, but was observed in monkeys receiving ipilimumab. Nivolumab in combination with 
ipilimumab was also associated with lymphoid hypocellularity of the cortex and/or medulla of 
the thymus and with acinar cell degranulation in the pancreas. Additional findings included 
interstitial mononuclear cell infiltrates in the kidneys, portal mononuclear cell infiltrates in the 
liver and myeloid hypercellularity in the bone marrow. Nivolumab in combination with 
ipilimumab at the high-dose level (ie, 50 mg/kg and 10 mg/kg, respectively) was associated with 
the death of 1 animal, attributed to acute gastric dilatation without histopathological evidence of 
colitis upon pathology evaluation of the GI tract.
1.1.8.2
Summary of Safety
Ipilimumab Monotherapy
Ipilimumab 3 mg/kg is globally approved for advanced melanoma based on the results of a phase 
study, MDX010-20. In MDX010-20, the ipilimumab monotherapy arm was administered 
3 mg/kg ipilimumab every 3 weeks for four doses. In this arm, there were 79% drug related 
adverse events, with 21% being Grade 3/4 and 3/131 (2%) Grade 5. The most frequent adverse 
events 
of 
interest 
were 
rash (30%), 
pruritis (33%), 
diarrhea (33%), 
colitis (8%), 
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endocrine disorders (9%), AST/ALT increased (2%), and hepatitis (1%). Any grade immune 
related adverse events were 60% and the Grade 3/4 immune related adverse events for the same 
cohort was 13% with the most frequent adverse events being diarrhea (5%), colitis (5%), 
rash (2%), and endocrine disorders (3%).
Additional details on the safety profile of ipilimumab, including results from other clinical 
studies, are also available in the ipilimumab IB.
Nivolumab Monotherapy
CA209003 is an ongoing Phase 1 open label, multiple dose escalation study in 306 subjects with 
select previously treated advanced solid tumors, including melanoma, RCC, NSCLC, colorectal 
cancer, and hormone-refractory prostate cancer. Subjects received nivolumab at doses of 
0.1, 0.3, 1, 3, or 10 mg/kg intravenously every 2 weeks, up to a maximum of 2 years of total 
therapy. As of 18-Mar-2013, a total of 306 melanoma subjects were treated with nivolumab in 
the dose range of 0.1 - 10 mg/kg.
No maximal tolerated dose was identified in CA209003. The incidence, severity and relationship 
of AEs were generally similar across dose levels and tumor types. Nivolumab related AEs of any 
grade occurred in 75.2% of subjects. Of the 306 treated subjects, 303 (99.0%) subjects have at 
least 1 reported AE regardless of causality. The most frequently reported AEs were 
fatigue (54.9%), 
decreased 
appetite (35.0%), 
diarrhea (34.3%), 
nausea (30.1%), 
and 
cough (29.4%). Treatment-related AEs were reported in 230 (75.2%) of the 306 subjects. The 
most frequently reported treatment-related AEs were fatigue (28.1%), rash (14.7%), 
diarrhea (13.4%), and pruritus (10.5%). Most treatment-related AEs were low grade. 
Treatment-related high grade (Grade 3-4) AEs were reported in 52 (17.0%) of subjects. The most 
common treatment-related high grade AEs were fatigue (2.3%) and diarrhea (1%).
Drug-related SAEs occurred in 11.5% of subjects. Grade 3-4 drug-related SAEs reported in at 
least 
2 subjects 
included: 
diarrhea (3 subjects, 1.0%), 
pneumonitis (3 subjects, 1.0%), 
pneumonia (2 subjects, 0.7%), and lipase increased (2 subjects, 0.7%).
Select AE categories (events with a potential inflammatory mechanism requiring more frequent 
monitoring and/or unique intervention such as immunosuppressants and/or endocrine 
replacement therapy) include: GI AEs, pulmonary AEs, renal AEs, hepatic AEs, skin AEs, and 
endocrinopathies. In addition, Select AEs include a category for infusion reactions. Each 
category is composed of a discrete set of preferred terms, including those of greatest clinical 
relevance. These Select AEs are considered events of interest based on the mechanism of action 
and were previously referred to as immune-related AEs or immune-mediated AEs.
The 10 mg/kg cohort had numerically greater frequency of high-grade select AEs including the 
subcategories of endocrinopathies, GI, pulmonary, and infusion reactions (Table 1.1.8.2-1). Most 
high grade events resolved following the treatment guidelines for the treatment of pulmonary 
events, GI events, hepatic events, renal events, and endocrine events, respectively.
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Table 1.1.8.2-1:
Treatment-related Select Adverse Events by Treatment - All CTC Grades Reported in at Least 
10 Treated Subjects in CA209003
Preferred Term
0.1 mg/kg
n=17
0.3 mg/kg
n=18
1 mg/kg
n=86
3 mg/kg 
n=54
10 mg/kg 
n=131
Total
N=306
Any 
Grade
Grade 
3-4
Any 
Grade
Grad
e 3-4
Any 
Grade
Grade 
3-4
Any 
Grade
Grade 
3-4
Any 
Grade
Grade 
3-4
Any 
Grade
Grade 
3-4
Any Select AE
8 (47)
1 (5.9)
9 (50)
0
42 (49)
3 (4)
23 (43)
2 (4)
58 (44)
13 (10)
140 (46)
19 (6)
Any Endocrinopathies
4 (24)
0
2 (11)
0
9 (11)
0
4 (7)
0
10 (8)
3 (2)
29 (10)
3 (1)
Endocrinopathies 
Thyroid
3 (18)
0
2 (11)
0
9 (11)
4 (7)
0
8 (6)
2 (2)
26 (9)
2 (1)
Blood TSH increased
2 (12)
0
1 (6)
0
2 (2)
0
2 (4)
0
4 (3)
1 (1)
11 (4)
1 (0.3)
Hypothyroidism
1 (6)
0
1 (6)
0
5 (6)
0
1 (2)
0
3 (2)
1 (1)
11 (4)
1 (0.3)
Any Skin AEs
3 (18)
0
5 (28)
0
27 (31)
0
12 (22)
0
28 (21)
1 (1)
75 (25)
1 (0.3)
Rash
3 (18)
0
3 (17)
0
20 (23)
0
5 (9)
0
14 (11)
0
45 (15)
0
Pruritus
0
0
1 (6)
0
15 (17)
0
3 (6)
0
13 (10)
1 (1)
32 (11)
1 (0.3)
Any GI AE
1 (6)
0
2 (11)
0
19 (22)
0
7 (13)
0
14 (11)
3 (2)
43 (14)
3 (1)
Diarrhea
1 (6)
0
2 (11)
0
19 (22)
0
6 (11)
0
13 (10)
3 (2)
41 (13)
3 (1)
Any hepatic AE
0
0
2 (11)
0
8 (9)
0
3 (6)
2 (4)
5 (4)
2 (2)
18 (6)
4 (1)
ALT increased
0
0
1 (6)
0
6 (7)
0
1 (2)
0
3 (2)
1 (1)
11 (4)
1 (0.3)
Any Pulmonary AE
1 (6)
0
1 (6)
0
6 (7)
3 (4)
2 (4)
0
7 (5)
3 (2)
17 (6)
6 (2)
Pneumonitis
1 (6)
0
1 (6)
0
4 (5)
2 (2)
1 (2)
0
6 (5)
2 (2)
12 (4)
4 (1)
Other Select AE
0
0
1 (6)
0
3 (4)
0
3 (6)
0
8 (6)
2 (2)
15 (5)
2 (1)
Infusion-related 
reaction
0
0
1 (6)
0
3 (4)
0
3 (6)
0
5 (4)
0
12 (4)
0
Abbreviations: ALT: alanine aminotransferase, TSH: thyroid stimulating hormone
Source: Preliminary data, MDX1106-03. Clinical data cut-off date: 18-Mar-2013
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Treatment-related AEs leading to discontinuation were reported in 32 (10.5%) of the 306 treated 
subjects on CA209003. The most frequent of these were pneumonitis (8 subjects; 2.6%) and 
colitis (3 subjects; 1.0%).
There were 3 (1%) drug related deaths; each occurred after 
development of pneumonitis.
The Phase 3 dose for nivolumab monotherapy is 3 mg/kg. Additional details on the safety profile 
of nivolumab, including results from other clinical studies, are also available in the BMS-936558 
(nivolumab) IB.
Nivolumab Combined with Ipilimumab 
As of 15-Feb-2013, in the Phase 1 study CA209004 of 86 subjects with unresectable or 
metastatic melanoma, ascending doses of nivolumab have been studied as monotherapy in 
sequence 
with 
ipilimumab (N = 33) 
or 
in 
combination 
with 
ascending 
doses 
of 
ipilimumab (N = 53).
In the sequential cohorts, 1 mg/kg and 3 mg/kg nivolumab cohorts have been studied. Subjects 
were required to have prior ipilimumab and their last treatment must have occurred within 
4 - 12 weeks. As such, based on ipilimumab pharmacokinetics, pharmacodynamically active 
ipilimumab was present at the outset of treatment in all subjects. Based on this, the monotherapy 
safety profile in the sequential cohorts was expected to differ from the monotherapy safety 
profile reported in CA209003. Therefore, the most relevant safety data for nivolumab 
monotherapy is from CA209003 (described above). The pooled safety data from CA209004 is 
only provided below for reference.
In each of the combination cohorts in this multi-arm study, ipilimumab was administered once 
every 3 weeks for 4 doses with nivolumab administered once every 3 weeks for 8 doses. Starting 
at week 24, ipilimumab and nivolumab were administered once every 12 weeks for 8 doses. The 
three initial dose escalation cohorts consisted of Cohort 1 (nivolumab 0.3 mg/kg plus ipilimumab 
3 mg/kg; n = 14), Cohort 2 (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg; n = 17) and 
Cohort 3 (nivolumab 3 mg/kg plus ipilimumab 3 mg/kg; n = 6). The study was subsequently 
amended to include Cohort 2a which evaluated nivolumab 3 mg/kg plus ipilimumab 1 mg/kg 
(n = 16). Safety data were pooled to summarize the overall findings.
At least one AE, regardless of whether they were attributed to the therapy, has been reported in 
81 (94.2%) of the 86 subjects (Table 1.1.8.2-2). A numerically higher number of subjects in the 
combination therapy treatment groups experienced severe AEs, regardless of causality and 
treatment related, than those in the monotherapy treatment group.
In the combination treatment groups, the following dose-limiting toxicities (DLTs) were 
observed during the dose escalation in the combination cohorts:

Cohort 1: Grade 3 elevated AST/ALT (1 subject);

Cohort 2 : Grade 3 uveitis (1 subject) and Grade 3 elevated AST/ALT (1 subject);

Cohort 3: Grade 4 elevated lipase (2 subjects) and Grade 3 elevated lipase (1 subject).
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Based on these data, Cohort 2 was identified as the maximum tolerated dose (MTD) and 
Cohort 3 exceeded the MTD.
The most frequent treatment related AEs were rash (54.7%), pruritis (47.2%) and 
fatigue (37.7%). The most frequently reported treatment related severe AEs in the combination 
group were lipase and AST elevation (13.2% each), ALT elevation (11.3%), followed by 
diarrhea (5.7%) and rash (3.8%).
Treatment related serious adverse events (SAEs) were reported in 49% of patients in the 
combination treated subjects (N = 53) and were most frequently severe SAEs were: 
AST elevation (13.2%), ALT elevation (11.3%), lipase elevation (5.7%) and diarrhea, colitis and 
renal failure (3.8% each). Ten of the 53 (18.9%) treated subjects in the combination cohort 
discontinued therapy due treatment-related adverse events, the most frequent of which were 
ALT, AST elevation, lipase elevation, renal failure or pneumonitis. No drug-related deaths were 
reported.
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Table 1.1.8.2-2:
Summary of Adverse Events Reported in 10% of Subjects Treated with Nivolumab in Combination 
with Ipilimumab Compared to Sequential Nivolumab Monotherapy
No. of Subjects (N)
Combination Therapy
n=53
Sequential (Nivo Monotherapy)
n=33
Preferred Term
Regardless of Causality
Treatment-related
Regardless of Causality
Treatment-related
Any Grade
Grade 3-4
Any Grade
Grade 3-4
Any 
Grade
Grade 3-4
Any Grade
Grade 3-4
Any AE
52 (98.1)
38 (71.7)
49 (92.5)
28 (52.8)
29 (87.9)
11 (33.4)
24 (72.7)
6 (18.2)
Rash
32 (60.4)
3 (5.7)
29 (54.7)
2 (3.8)
7 (21.2)
0
3 (9.1)
0
Fatigue
31 (58.5)
0
20 (37.7)
0
12 (36.4)
14 (42.4)
3 (9.1)
0
Pruritus
28 (52.8)
1 (1.9)
25 (47.2)
0
6 (18.2)
6 (18.2)
0
Diarrhea
22 (41.5)
3 (5.7)
18 (34.0)
3 (5.7)
4 (12.1)
0
3 (9.1)
0
Cough
19 (35.8)
0
7 (13.2)
0
8 (24.2)
0
2 (6.1)
0
Nausea
19 (35.8)
1 (1.9)
11 (20.8)
0
6 (18.2)
0
1 (3.0)
0
Pyrexia
18 (34.0)
0
11 (20.8)
0
6 (18.2)
0
0
0
Headache
18 (34.0)
0
6 (11.3)
0
3 (9.1)
0
0
0
AST increased
13 (24.5)
8 (15.1)
11 (20.8)
7 (13.2)
1 (3.0)
0
0
0
Vomiting
13 (24.5)
3 (5.7)
6 (11.3)
1 (1.9)
1 (3.0)
0
0
0
ALT increased 
12 (22.6)
7 (13.2)
11 (20.8)
6 (11.3)
1 (3.0)
0
1 (3.0)
0
Abdominal pain
11 (20.8)
0
5 (9.4)
0
1 (3.0)
1 (3.0)
0
0
Arthralgia
11 (20.8)
0
4 (7.5)
0
7 (21.2)
1 (3.0)
3 (9.1)
0
Lipase increased
11 (20.8)
9 (17.0)
10 (18.9)
7 (13.2)
4 (12.1)
2 (6.1)
4 (12.1)
2 (6.1)
Constipation
10 (18.9)
0
0
0
4 (12.1)
0
1 (3.0)
0
Back pain
9 (17.0)
0
0
0
4 (12.1)
0
0
0
Decreased appetite
9 (17.0)
0
5 (9.4)
0
3 (9.1)
0
1 (3.0)
0
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Table 1.1.8.2-2:
Summary of Adverse Events Reported in 10% of Subjects Treated with Nivolumab in Combination 
with Ipilimumab Compared to Sequential Nivolumab Monotherapy
No. of Subjects (N)
Combination Therapy
n=53
Sequential (Nivo Monotherapy)
n=33
Preferred Term
Regardless of Causality
Treatment-related
Regardless of Causality
Treatment-related
Any Grade
Grade 3-4
Any Grade
Grade 3-4
Any 
Grade
Grade 3-4
Any Grade
Grade 3-4
Dyspnea
9 (17.0)
1 (1.9)
3 (5.7)
0
3 (9.1)
1 (3.0)
0
0
Chills
9 (17.0)
0
3 (5.7)
0
2 (6.1)
0
0
0
Amylase increased
9 (17.0)
3 (5.7)
8 (15.1)
3 (5.7)
1 (3.0)
1 (3.0)
1 (3.0)
1 (3.0)
Pain in extremity
7 (13.2)
0
0
0
2 (6.1)
0
0
0
Abbreviations: AE: adverse event, ALT: alanine aminotransferase, AST: aspartate aminotransferase
Source: Preliminary data, MDX1106-04. Clinical cut-off date 15-Feb-2013.
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nivolumab / ipilimumab
Treatment-related AEs of Special Interest: A greater number of treatment-related Select AEs 
including pulmonary AEs, GI AEs, hepatic AEs, endocrinopathy, skin AEs, renal AEs, and 
others, 
provided 
in 
Table 
1.1.8.2-3, 
were 
reported 
in 
subjects 
treated 
with 
nivolumab + ipilimumab combination therapy than in sequential nivolumab monotherapy.
The most frequently reported treatment-related Select AEs in the combination therapy group 
included rash, pruritus, diarrhea, AST increased, and ALT increased. With the exception of 
hepatic AEs, the events were reported were Grade 1-2. Isolated cases of pneumonitis and uveitis 
were observed, a finding that is consistent with previous experience with monotherapy.
The most frequently reported treatment-related Select AEs in the monotherapy treatment group 
were pruritus, rash, and diarrhea; all were Grade 1-2.
Table 1.1.8.2-3:
Summary of Treatment-related Events of Special Interest Reported 
in at Least 2 Subjects Treated with Nivolumab in Combination with 
Ipilimumab Compared to Sequential Nivolumab Monotherapy
No. of Subjects (N)
Preferred Term
Combination Therapy
n=53
Sequential (Nivo Monotherapy)
n=33
Any Grade
Grade 3-4
Any Grade
Grade 3-4
Any pulmonary AEs
3 (5.7)
1 (1.9)
1 (3.0)
0
Pneumonitis
3 (5.7)
1 (1.9)
1 (3.0)
0
Any GI AE
20 (37.7)
5 (9.4)
3 (9.1)
0
Colitis
5 (9.4)
2 (3.8)
0
0
Diarrhea
19 (35.8)
3 (5.7)
3 (9.1)
0
Any hepatic AE
12 (22.6)
8 (15.1)
1 (3.0)
0
ALT increased
11 (20.8)
6 (11.3)
1 (3.0)
0
AST increased
11 (20.8)
7 (13.2)
0
0
Any endocrinopathy
7 (13.2)
1 (1.9)
3 (9.1)
1 (3.0)
Adrenal insufficiency
2 (3.8)
0
1 (3.0)
1 (3.0)
Hyperthyroidism
2 (3.8)
0
0
0
Hypophysitis
2 (3.8)
1 (1.9)
2 (6.1)
1 (3.0)
Hypothyroidism
2 (3.8)
0
2 (6.1)
1 (3.0)
Thryoiditis
3 (5.7)
0
0
0
Any skin AE
37 (69.8)
2 (3.8)
8 (24.2)
0
Pruritus
25 (47.2)
0
6 (18.2)
0
Rash
29 (54.7)
2 (3.8)
3 (9.1)
0
Any Renal AE
3 (5.7)
3 (5.7)
0
0
Blood creatinine 
increased
3 (5.7)
3 (5.7)
0
0
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Table 1.1.8.2-3:
Summary of Treatment-related Events of Special Interest Reported 
in at Least 2 Subjects Treated with Nivolumab in Combination with 
Ipilimumab Compared to Sequential Nivolumab Monotherapy
No. of Subjects (N)
Preferred Term
Combination Therapy
n=53
Sequential (Nivo Monotherapy)
n=33
Any Grade
Grade 3-4
Any Grade
Grade 3-4
Renal failure acute
2 (3.8)
2 (3.8)
0
0
Other
1 (1.9)
0
0
0
Infusion-related reaction 
1 (1.9)
0
0
0
Abbreviations: AE: adverse event, ALT: alanine aminotransferase, AST: aspartate aminotransferase, ipi: 
ipilimumab, nivo: nivolumab
Source: Preliminary data, MDX1106-04. Clinical cut-off date 15-Feb-2013.
Recently, data from a Phase 1 study of nivolumab in combination with ipilimumab in metastatic 
renal cell carcinoma (mRCC) showed an incidence of 28.6% grade 3-4 treatment related adverse 
events for patients treated at nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, while patients treated 
at nivolumab 1 mg/kg plus ipilimumab 3 mg/kg had grade 3-4 treatment related adverse events 
in 60.9%.9 Median PFS based on an interim analysis was in the same range for both dose levels.
Adverse Event Management Algorithms
Because of the potential for clinically meaningful nivolumab or ipilimumab related AEs 
requiring early recognition and prompt intervention, management algorithms have been 
developed for suspected pulmonary toxicity, GI, hepatotoxicity, endocrinopathy, skin toxicity, 
neurological toxicity, and nephrotoxicity. The algorithms recommended for utilization in 
CA209032 are contained in Appendix 2.
1.1.8.3
Summary of Clinical Activity
Ipilimumab Monotherapy
In melanoma, two completed Phase 3 studies have demonstrated clinically meaningful and 
statistically significant survival benefit in advanced melanoma. The completed Phase 3 study 
MDX010-20 demonstrated improved survival in pre-treated advanced melanoma. The study 
compared the overall survival (OS) of ipilimumab (3 mg/kg) plus a melanoma-specific vaccine 
(gp100) to that of gp100 alone. A second comparison defined the OS of ipilimumab alone 
vs gp100 alone. Both comparisons demonstrated statistically significant improvements in 
OS (p = 0.0004 and 0.0026, respectively). The median OS was 10, 10.1, and 6.4 months, for
ipilimumab plus gp100, ipilimumab monotherapy, and gp100 monotherapy, respectively. The 
objective response rate was 5.7% (95% CI: 3.7, 8.4), 10.9% (95% CI: 6.3, 17.4), and 
1.5% (95% CI: 0.2, 5.2) on the ipilimumab arm, the ipilimumab plus gp100 arm, and the 
gp100 arm, respectively.
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BMS-936558 / BMS-734016
nivolumab / ipilimumab
The completed Phase 3 study CA184024 demonstrated improved survival in treatment-naive 
melanoma. The study compared the OS of ipilimumab (10 mg/kg) plus dacarbazine 
vs dacarbazine plus placebo. OS was improved in the ipilimumab plus dacarbazine group 
compared to the dacarbazine plus placebo group (11.2 months vs 9.1 months, respectively, 
HR 0.72, p < 0.001). The objective response rate was 15.2% on the ipilimumab plus dacarbazine 
arm compared to 10.3% on the dacarbazine plus placebo arm.
The approved ipilimumab regimen in advanced melanoma is 3 mg/kg ipilimumab monotherapy.
Nivolumab Monotherapy
In CA209003 (MDX1106-03), the clinical activity of nivolumab was demonstrated in a variety 
of tumor types and across a range of doses (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg). 
As of the clinical cut-off date of 05-Mar-2013, a total of 306 subjects with melanoma, RCC, and 
NSCLC have been treated with nivolumab. All subjects initiated treatment at least one year prior 
to analysis. A response of either CR or PR, as determined by investigator assessed tumor 
evaluations based on modified RECIST 1.0, has been reported at all dose levels.
Among 107 patients with advanced melanoma who received nivolumab, the preliminary 
objective response rate was 33/107 (31%). Responses occurred at each dose level, with 
6/17 (35%), 5/18 (28%), 11/35 (31%), 7/17 (41%), and 4/20 (20%) melanoma subjects 
responding at 0.1, 0.3, 1, 3, and 10 mg/kg, respectively. Duration of response range from 
24.1 to 48.7+, 18.4 to 66.3+, 32.4 to 108.1+, 40.1+ to 115.4+, and 73.9 to 117.0+ months in 
melanoma subjects treated at 0.1, 0.3, 1, 3, and 10 mg/kg, respectively. An additional 7% of 
melanoma subjects had stable disease for 24 weeks or longer. Across dose levels, melanoma 
subjects achieved a median overall survival of 16.8 months (95% CI: 12.5, 31.6), with a 
2-year overall survival rate of 43%.
Nivolumab Combined with Ipilimumab
As of 15-Feb-2013, in the combination cohorts of CA209004, ipilimumab was administered once 
every 3 weeks for 4 doses with nivolumab administered once every 3 weeks for 8 doses. Starting 
at week 24, ipilimumab and nivolumab were administered once every 12 weeks for 8 doses. 
The three initial dose-escalation cohorts consisted of Cohort 1 (nivolumab 0.3 mg/kg plus 
ipilimumab 3 mg/kg; n = 14), Cohort 2 (nivolumab 1.0 mg/kg plus ipilimumab 3 mg/kg; n = 17) 
and Cohort 3 (nivolumab 3.0 mg/kg plus ipilimumab 3 mg/kg; n = 6). Later, the study was 
amended to include Cohort 2a which evaluated nivolumab 3 mg/kg plus ipilimumab 1 mg/kg 
(n = 15).
In the combination cohorts, across all dose levels (N = 53), confirmed objective responses 
according to modified WHO criteria were observed in 21 of 52 patients (40%; 95% CI, 27 to 55) 
who had a response that could be evaluated. In addition, 4 patients had an objective response 
according to immune-related response criteria and 2 had an unconfirmed partial response. These 
patients were not included in the calculation of objective response rates. In the 1 mg/kg 
nivolumab + 3 mg/kg ipilimumab group, the ORR was 53% (see Table 1.1.8.3-1).
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Table 1.1.8.3-1:
Objective Response Rate and Progression Free Survival 24 Weeks 
Rate in Melanoma Subjects - MDX1106-04
Treatment Groupa
Nivo Dose 
(mg/kg)
N
ORR
95% CI of 
ORR
PFS at 24 
weeks (%)
95% CI of 
PFS
Nivo + 3 Ipi
0.3
14
3 (21)
5 - 51
43
17 - 69
Nivo + 3 Ipi
1.0
17
9 (53)
28 - 77
58
34 - 82
Nivo + 1 Ipi
3.0
15
6 (40)
16 - 68
59
26 - 92
Nivo + 3 Ipi
3.0
6
3 (50)
12 - 88
50
10 - 90
a Subjects received ipilimumab immediately prior to study entry, within 4 - 12 weeks of initiating nivolumab 
monotherapy on the protocol.
Abbreviations: CI: confidence interval, Ipi: ipilimumab, Nivo: nivolumab, ORR: objective response rate, PFS: 
progression-free survival
Source: Preliminary data, MDX1106-04. Clinical cut-off date 15-Feb-2013.
After noting that several patients had very deep responses (approaching complete response), a 
post hoc analysis of the number of patients with tumor reduction of 80% or more was done 
(Figure 1.1.8.3-1 and Figure 1.1.8.3-2). This depth of response was uncommon in published 
studies of ipilimumab or nivolumab.2,34 A total of 16 out of 52 evaluable patients had tumor 
reduction of 80% or more at 12 weeks, including 5 with a complete response.
In the combination cohorts, overall evidence of clinical activity (conventional, unconfirmed, or 
immune-related response or stable disease for 24 weeks) was observed in 65% of patients 
(95% CI, 51 to 78). Responses were ongoing in 19 of 21 patients who had a response, with the 
duration ranging from 6.1 to 72.1 weeks at the time of data analysis.82
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Representative spider plots in Figure 1.1.8.3-1 show changes from baseline in the tumor burden, 
measured as the sum of the products of perpendicular diameters of all target lesions, in patients 
who received the concurrent regimen of nivolumab (at a dose of 1 mg per kilogram of body 
weight) and ipilimumab (3 mg per kilogram), the maximum doses that were associated with an 
acceptable level of adverse events. Triangles indicate the first occurrence of a new lesion. 
Dashed lines indicate 50% and 80% improvement from baseline (gray line) in target lesions, as 
assessed by means of modified World Health Organization criteria. Figure 1.1.8.3-2 shows a 
representative waterfall plot of the maximum percentage change in target lesions, as compared 
with baseline measurements, in patients who received the concurrent regimen. A total of 
47 patients had a response that could be evaluated in this analysis; 46 had a positive or negative 
change in target lesions from baseline, and 1 had no change. The dashed line denotes 80% tumor 
reduction in target lesions from baseline.83
1.1.9
Rationale to Support Dose/Schedule of Nivolumab Combined with 
Ipilimumab
In CA209004, the 3 mg/kg nivolumab plus 3 mg/kg ipilimumab dosing regimen exceeded the 
maximum tolerated dose per protocol. In CA209004, while both Cohort 2 (1 mg/kg nivolumab 
plus 3 mg/kg ipilimumab) and Cohort 2a (3 mg/kg nivolumab plus 1 mg/kg ipilimumab) had 
similar Week 24 PFS rate, a dose of 3 mg/kg of ipilimumab every 3 weeks for a total of 
four doses and 1 mg/kg nivolumab every 3 weeks for four doses followed by nivolumab 3 mg/kg 
every 2 weeks until progression was chosen. Based on preliminary data, this group had a 
numerically higher ORR than Cohort 2a, although the significance of this difference is not clear.
The rationale for maximizing the ipilimumab dose over the nivolumab dose is primarily based on 
a well-defined dose and exposure response for ipilimumab (10 mg/kg > 3 mg/kg > 0.3 mg/kg). 
In contrast, analysis of nivolumab monotherapy across dose ranges of 1 mg/kg to 10 mg/kg 
reveals similar clinical activity with no clear evidence of dose or exposure response. Therefore, 
the selection of 3 mg/kg of ipilimumab (Cohort 2) may be more clinically impactful than 
selection of 3 mg/kg of nivolumab (Cohort 2a).
The combination arm in Study CA209032 is expected to use the same dose and schedule as that 
in Cohort 2 of CA209004 for the first 12 weeks (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg). 
This is the same regimen currently being studied in the Phase 3 study in advanced melanoma, 
CA209067 and in ongoing studies in RCC and NSCLC. In CA209067 and in this current 
protocol, ipilimumab will be limited to 4 doses in the first 12 weeks since this is the currently 
approved dosing regimen.
To ensure that this regimen is tolerable across other tumors, an initial dose escalating safety 
evaluation step for the combination arm will be instituted. The starting dose in this evaluation 
will be 1 mg/kg each nivolumab and ipilimumab. If this regimen is tolerable, then Dose level 2, 
1 mg/kg nivolumab + 3 mg/kg ipilimumab will be evaluated. The criteria for determining 
tolerability are based on the AE profile observed for the combination in CA209004.
Recently, data from a Phase 1 study of nivolumab in combination with ipilimumab in metastatic 
renal cell carcinoma (mRCC) showed an incidence of 28.6% grade 3-4 treatment related adverse 
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
events for patients treated at nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, while patients treated 
at nivolumab 1 mg/kg plus ipilimumab 3 mg/kg had grade 3-4 treatment related adverse events 
in 60.9%.9 Median PFS based on an interim analysis was in the same range for both dose levels. 
Similarly, data from a Phase 1 study of nivolumab in combination with ipilimumab in first line 
NSCLC patients showed that the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg dose level was 
well tolerated while sustaining clinical activity.10 Based on these data, Study CA209032 will also 
investigate the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg dose level.
Based on the clinical activity in CA209004, the majority of responses to the combination of 
nivolumab and ipilimumab occur in the first 12 weeks. Nivolumab 3 mg/kg monotherapy 
treatment every two weeks until progression was studied in CA209003 and was associated with 
durable responses. Thus, starting at week 12, which is after the completion of the four doses of 
combined nivolumab and ipilimumab, nivolumab at 3 mg/kg will be administered every 
two weeks until progression.
In summary, nivolumab and ipilimumab combinations have shown additive or synergistic 
activities across the tumor types investigated. To further improve the tolerability profile, other 
combination dosing regimens were also explored in the nivolumab development program. Less 
frequent dosing of ipilimumab at 1 mg/kg q6week when given with nivolumab 3 mg/kg q2week 
was found to have a similar discontinuation rate to that observed in nivolumab monotherapy 
(11% vs 10%) while yielding a ORR of 39% and a 12-month PFS rate of 35% in preliminary 
data from CA209012 in NSCLC. The median OS was 18.1 months. Based on these efficacy and 
safety data, nivolumab 3 mg/kg q 2 weeks + ipilimumab 1 mg/kg q 6 weeks dosing regimen will 
be evaluated in the current study.
1.1.10
Rationale for Shorter Nivolumab and Ipilimumab Infusion Times in 
Additional Pancreatic Cancer Cohort
Long infusion times place a burden on patients and treatment centers. Establishing that 
nivolumab and ipilimumab can be safely administered using shorter infusion times of 
approximately 30 minutes duration in subjects will diminish the burden provided no change in 
safety profile. Previous clinical studies of nivolumab monotherapy and ipilimumab monotherapy 
and the combination of nivolumab and ipilimumab have used a 60 minute infusion duration for 
nivolumab and 90 minute infusion duration for ipilimumab (1 - 3 mg/kg dosing for both). 
However, both nivolumab and ipilimumab have been administered at up to 10 mg/kg with the 
same infusion duration.

Nivolumab has been administered safely over 60 minutes at doses ranging up to 10 mg/kg 
safely over long treatment duration. In Study CA209010, (a Phase 2, randomized, double 
blinded, dose-ranging study of nivolumab in subjects with advanced/metastatic clear cell 
RCC) a dose association was observed for infusion site reactions and hypersensitivity 
reactions (1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg and 18.5% at 10 mg/kg). All the events were 
Grade 1 - 2 and were manageable. An infusion duration of approximately 30 minutes for 3 
mg/kg nivolumab (30% of the dose provided at 10 mg/kg) is not expected to present any 
safety concerns compared to the prior experience at 10 mg/kg nivolumab dose infused over a 
60 minute duration.
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab

Similarly, ipilimumab at 10 mg/kg has been safely administered over 90 minutes. In the 
CA184022 study, where ipilimumab was administered up to a dose of 10 mg/kg, on-study 
drug related hypersensitivity events (Grade 1 - 2) were reported in 1 (1.4%) subject in the 0.3 
mg/kg and in 2 (2.8%) subjects in the 10 mg/kg group. There were no drug-related 
hypersensitivity events reported in the 3 mg/kg group. Across the 3 treatment groups, no 
Grade 3 - 4 drug-related hypersensitivity events were reported and there were no reports of 
infusion reactions. Ipilimumab 10 mg/kg monotherapy has also been safely administered as 
90 minute infusion in large phase 3 studies in prostate cancer (CA184043) and as adjuvant 
therapy for stage 3 melanoma (CA184029), with infusion reactions occurring in subjects. 
Administering 1 mg/kg of ipilimumab represents one-tenth of the 10 mg/kg dose.
Overall, infusion reactions including high-grade hypersensitivity reactions have been uncommon 
across nivolumab or ipilimumab clinical studies or the combination of nivolumab and 
ipilimumab. Furthermore, a 30-minute break after the first infusion for the combination cohort 
will ensure the appropriate safety monitoring before the start of the second infusion. Overall, a 
change in safety profile is not anticipated with 30-minute infusion of nivolumab, ipilimumab or 
combination.
Shortened infusion times will be implemented only in the additional re-opened pancreatic cancer
cohort.
1.1.11
Rationale for Permitting Continued Treatment in Select Cases of 
Progressive Disease
Accumulating clinical evidence indicates some subjects treated with immune system stimulating 
agents may develop progression of disease (by conventional response criteria) before 
demonstrating clinical objective responses and/or stable disease. This phenomenon was observed 
in approximately 10% of subjects in the Phase 1 study of nivolumab and has also been reported 
for ipilimumab monotherapy.84 Two hypotheses have been put forth to explain this phenomenon. 
First, enhanced inflammation within tumors could lead to an increase in tumor size which would 
appear as enlarged index lesions and as newly visible small non-index lesions. Over time, both 
the malignant and inflammatory portions of the mass may then decrease leading to overt signs of 
clinical improvement. Alternatively, in some individuals, the kinetics of tumor growth may 
initially outpace anti-tumor immune activity. With sufficient time, the anti-tumor activity will 
dominate and become clinically apparent. Therefore, subjects will be allowed to continue study 
therapy after initial investigator-assessed RECIST 1.1 defined progression if they are assessed to 
be deriving clinical benefit and tolerating study drug (Section 4.5.7). Such subjects must 
discontinue study therapy upon evidence of further progression.
1.2
Research Hypothesis 
Treatment with nivolumab monotherapy, nivolumab combined with ipilimumab, or nivolumab 
combined with ipilimumab and cobimetinib will have clinical activity in subjects with advanced 
or metastatic tumors.
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
The combination of nivolumab and ipilimumab has the potential for increased benefit compared 
to both ipilimumab monotherapy and nivolumab monotherapy. In Study CA209004, 53% of the 
subjects with advanced melanoma treated at the dose level of nivolumab 1 mg/kg combined with 
ipilimumab 3 mg/kg had an objective response, the majority of which had deep tumor reduction 
of 80% or more. This deep response compares favorably to results with 3 mg/kg ipilimumab 
monotherapy or nivolumab monotherapy and is the basis for an ongoing randomized 
Phase 3 study in advanced melanoma (CA209067). Studies investigating the efficacy and safety 
of nivolumab in combination with ipilimumab are ongoing in NSCLC and RCC.
The combination of nivolumab and ipilimumab has the potential for increased frequencies of 
adverse events compared to ipilimumab monotherapy or nivolumab monotherapy. The most 
common (reported at > 10% incidence) treatment related AEs are fatigue, rash, pruritus, diarrhea, 
lipase increased, pyrexia, ALT increase, AST increased, amylase increased, and vitiligo. 
This class of AEs are expected for the combination of nivolumab and ipilimumab based on the 
known AE profile of each drug alone. In addition, many of the Grade 3-4 adverse events were 
laboratory in nature (ie, LFTs, lipase, amylase), were without clinical sequalae and have been 
manageable and reversible following intervention dose delays or with systemic steroid treatment. 
However, these AEs have the potential to be fatal if not detected early and managed per the 
established algorithm and fatal AEs have been reported for both ipilimumab and nivolumab 
monotherapy. As of June 2013, one subject died because of a study treatment related adverse 
event (toxic epidermal necrolysis, TEN) in the nivolumab + ipilimumab development program. 
Fatal TEN has previously been reported for ipilimumab monotherapy.
Evaluating nivolumab monotherapy and the combination of nivolumab and ipilimumab in 
subjects with advanced or metastatic solid tumors for which no standard of care in advanced 
lines of treatment exists, will potentially generate efficacy signals as a basis for further clinical 
development in these tumor types.
Across multiple tumors, 3 mg/kg nivolumab as well as 3 mg/kg ipilimumab monotherapy have
demonstrated a tolerable AE profile in hundreds, respectively thousands of subjects that appears 
to be independent of tumor type. The combination of 1 mg/kg nivolumab + 3 mg/kg ipilimumab 
has demonstrated an acceptable AE profile in melanoma and is currently in Phase 3. The same 
regimen is currently being studied in RCC and NSCLC. The following safety measures have 
been employed to ensure safety of the subjects in this current study:

Intense toxicity monitoring will help to ensure the subjects’ safety in Study CA209032, 
including frequent safety conference calls with investigators and representatives of the 
sponsor

A BMS medical safety team (MST) routinely reviews safety signals across the entire 
nivolumab program, including all ongoing combinations with ipilimumab

Two stage design used which will stop an individual arm for lack of sufficient activity

For the combination arm, an initial dose escalating safety evaluation phase will be performed 
to determine the optimal dose for each tumor type independently
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Cobimetinib as monotherapy or in combination with other targeted therapy is well tolerated.86
Safety data from the Phase 3 coBRIM trial demonstrated that the combination of vemurafenib 
and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of 
Grade 3 or higher, as compared with vemurafenib and placebo (65% vs 59%).87 The 
recommended dosage of oral cobimetinib is 60 mg once daily for 21 consecutive days, followed 
by a 7-day break, for a total cycle length of 28 days. 
Emerging preliminary data on safety and efficacy of the PD-1 inhibitor atezolizumab in 
combination with cobimetinib in advanced CRC have demonstrated a clinical benefit and was 
well tolerated.56 Being a PD-1 inhibitor, nivolumab is expected to have an acceptable tolerability 
profile in combination with cobimetinib similar to that of atezolizumab.
Given that the toxicity profile of the combination of nivolumab and ipilimumab is well-
characterized and that cobimetinib does not have overlapping toxicity profiles with nivolumab or 
ipilimumab, the combination of these three agents is not expected to increase frequency and/or 
severity of drug associated toxicities.
Based on the above assessment, the potential benefit of combining nivolumab with ipilimumab 
and cobimetinib appears to outweigh the potential risk. The overall risk/benefit assessment 
supports the evaluation of these combinations in this setting.
In conclusion, the overall risk-benefit assessment for Study CA209032 does justify the conduct 
of the trial.
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Council for 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.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment).
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2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. 
The investigator or BMS should also provide the IRB/IEC with a copy of the Investigator 
Brochure or product labeling information to be provided to subjects and any updates.
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate.
In situations where consent cannot be given to subjects, their legally acceptable representatives 
are clearly and fully informed about the purpose, potential risks, and other critical issues 
regarding clinical studies in which the subject volunteers to participate.
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
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 the informed 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 completed for 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 his 
or her informed consent during the study, 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 
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subject's willingness to continue participation in the study. This communication should be 
documented.
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF 
and, in the US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records.
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
This is a multicenter Phase 1/2, two stage, open label study of nivolumab monotherapy, 
nivolumab combined with ipilimumab, in adult (18 years) subjects with advanced or metastatic 
cancer of one of the following tumor types:
1) Triple Negative Breast Cancer (TNBC)
2) Gastric Cancer (GC)
3) Pancreatic Cancer (PC)
4) Small Cell Lung Cancer (SCLC)
5) Bladder Cancer (BC)
6) Ovarian Cancer (OC)
Or nivolumab combined with ipilimumab and cobimetinib in adult (18 years) subjects from the 
additional pancreatic cancer cohort only.
Treatment assignment: The assignment to treatment arm and evaluation of safety and activity 
will be performed independently for each tumor type (Figure 3.1-1). For each tumor type, 
subjects will be assigned (described in Section 4.3.4) to one of the following treatment arms:
Arm N:
Nivolumab monotherapy (3 mg/kg) Q2W
Arm N-I Dose Level 1:
Nivolumab (1 mg/kg) + ipilimumab (1 mg/kg) Q3W for 4 doses, 
then nivolumab (3mg/kg) Q2W
Arm N-I Dose Level 2:
Nivolumab (1 mg/kg) + ipilimumab (3 mg/kg) Q3W for 4 doses, 
then nivolumab (3 mg/kg) Q2W
Arm N-I Dose Level 2b:
Nivolumab (3 mg/kg) + ipilimumab (1 mg/kg) Q3W for 4 doses, 
then nivolumab (3 mg/kg) Q2W
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Arm N-I Dose Level 2c:
Nivolumab (3 mg/kg) Q2W + ipilimumab (1 mg/kg) Q6W
Arm N-I Dose Level 2d:
Nivolumab 3 mg/kg Q2W + ipilimumab (1 mg/kg) Q6W + 
cobimetinib 60 mg po qd 21 days on/7 days off for the additional
pancreatic cancer cohort only
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Dose-escalation Safety Evaluation Phase for Combination Arm: Although the regimen 
currently used in the Phase 3 melanoma study, nivolumab 1 mg/kg IV + ipilimumab 3 mg/kg, 
was expected to also be tolerable in the tumors studied here, an initial dose-escalating safety 
evaluation for the combination arms was conducted with GC, PC, TNBC, or SCLC (described in 
protocol Section 3.1.2). The BC cohort was added to this protocol following the completion of 
the safety evaluations in GC, PC, TNBC, and SCLC at dose level 1 (nivolumab 1 mg/kg, 
ipilimumab 1 mg/kg) which did not reveal safety concerns. Thereby the starting dose level for 
the BC cohort was dose level 2 (nivolumab 1 mg/kg, ipilimumab 3 mg/kg). Six BC patients were 
initially randomized to Dose Level 2, after which enrollment to Dose Level 2b (nivolumab 
3 mg/kg, ipilimumab 1 mg/kg) began.
Enrollment to Stage 1 for Arm N occurred in parallel to the safety evaluation for Arm N-I.
Two Stage Design: GC, PC, TNBC, SCLC Arms will follow a two-stage design to test whether 
nivolumab monotherapy or nivolumab combined with ipilimumab yields an objective response 
rate (ORR) that is of clinical interest in the investigated tumor types. For each tumor type, only 
treatment arms which meet an ORR threshold will proceed from Stage 1 to Stage 2 (described in 
protocol Section 3.1.3). Enrollment to Stage 2 in a given treatment arm can continue even if the 
other treatment arm is still in Stage 1.
For Stage 2, upon completion of enrollment for the initial 40 subjects, additional subjects may be 
assigned into Arm N and Arm N-I up to a total of 100 subjects (including those assigned in 
Stage 1) in each treatment arm of the given tumor type. For tumor types where nivolumab 
monotherapy or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg proceeded to Stage 2, assessment 
of Dose Level 2b in Stage 2 (nivolumab 3 mg/kg + ipilimumab 1 mg/kg, n=up to 70 subjects) 
may be initiated for that tumor type. For SCLC, an additional 250 subjects (second- or third-line) 
will be randomized in a 3:2 ratio to one of the 2 expansion groups: nivolumab 3 mg/kg every 
2 weeks or nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks for 4 cycles followed by 
nivolumab 3 mg/kg.
3.1.1
Modified Designs
Bladder Cancer Cohort
The enrollment for the BC cohorts N and N-I (Dose Level 2b) will be conducted as a One Stage 
Design:

Recently, inhibition of PD-L1 by MPDL3280A was shown to have clinical activity in 
patients with metastatic urothelial bladder cancer, leading to approval of the drug in this 
indication by the FDA.88 The overall response rate in all treated subjects was 15%.

Nivolumab has recently demonstrated meaningful antitumor activity with an overall response 
rate of 19.6% in all treated subjects

As these data show that checkpoint inhibition has potential to be an active treatment for 
patients with advanced bladder cancer, a Two Stage design with the intent of avoiding to 
expose too many patients to a potentially ineffective treatment does not appear to be 
necessary for this specific tumor type.66
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
Bladder arms N and N-I (Dose Levels 2 and 2b) will be conducted as a One Stage Design 
with the treatment of 26-105 subjects in each arm. The Safety Evaluation Phase for the N-I 
arm will start at Dose Level 2 (nivolumab 1 mg/kg, ipilimumab 3 mg/kg) and will evaluate 
safety and tolerability after the first 6 randomized subjects. Following the N-I safety 
evaluation phase, Dose Levels 2 will treat approximately 92 subjects and 2b will treat up to a 
total of 105 subjects. Based on the safety evaluations thus far on study, no dose escalation 
phase is necessary for bladder cohort N-I Dose Level 2b (nivolumab 3 mg/kg, 
ipilimumab 1 mg/kg). 
Ovarian Cancer Cohort
The OC cohorts N-I (Dose Level 2, 2b, 2c) will be conducted as a One Stage Design with the 
enrollment of 40 subjects in each arm. The Dose Level 2c was added to Ovarian Cancer Cohort 
based on the results of CA209003 and CA209012 clinical studies mentioned above. The efficacy 
and tolerability of nivolumab monotherapy observed in CA209003 study with longer follow-up 
of previously treated NSCLC patients suggested a strategy in which nivolumab serves as the 
“base” of a combination regimen, with ipilimumab exposure limited by lower doses and/or less 
frequent administration. This strategy is the basis for new nivolumab and ipilimumab
combination regimens with nivolumab 3 mg/kg Q2W combined with ipilimumab 1 mg/kg Q6W. 
This regimen was used in CA209012 study with preliminary data showing a promising activity 
and a good safety profile of the combination.
The enrollment to the N-I arm to Dose Levels 2, 2b, and 2c will be conducted simultaneously. 
Due to the low risk of development of new safety signals on the combination arms confirmed by 
the additional information from the combination studies in melanoma, lung, renal cell carcinoma, 
and glioblastoma as well as the clinical study with ipilimumab 10 mg/kg monotherapy in ovarian 
cancer, which did not reveal any new safety signals (please refer to Section 1.1 Study Rationale
and Sections 5.5.1.2, 5.5.2.2, 5.5.3.2, 5.5.4.2, and 5.6.1.3 in the current version of the 
Investigator Brochure), no Safety Evaluation Phase will be employed. Ovarian cancer subjects 
will be followed for related toxicities and decisions to stop treatment will be made on an ongoing 
basis.
Additional Pancreatic Cancer Cohort
Enrollment in the PC cohort will be initiated for one dose level N-I in combination with 
cobimetinib (Dose Level 2d) and will be conducted as a One-Stage Design:
The safety profile of all agents proposed for the triplet combination are well defined as either 
monotherapy or in combination and the products are already commercially available for the 
treatment of several advanced and metastatic tumor types. The safety profile of the combination 
of nivolumab with ipilimumab (3 mg/kg) is well characterized and it is approved for treatment of 
unresectable or metastatic melanoma. The toxicity profile of the nivolumab + ipilimumab 
combination has been shown to correlate with the ipilimumab dose: With increasing doses of 
ipilimumab there has been an increase in frequency of adverse events, and potentially the 
severity of these events, however no novel toxicities have been demonstrated versus either agent 
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alone.82,89,90,91,92 In the current regimen for this protocol cohort, the dose of ipilimumab will be 
cumulatively lower than on prior cohorts studied in the proposed indication as well as the 
approved dose level for the combination for the treatment of advanced and metastatic melanoma. 
The toxicity profile with lower doses of ipilimumab has been established to be very similar to 
that of nivolumab monotherapy.93
The safety of a PD-L1 agent combined with cobimetinib is already established and safe. For the 
triplet combination, non-overlapping toxicities are expected. Therefore, if there were to be an 
increase in toxicity, no new toxicities are anticipated and it is not expected to be significantly 
different that that seen in the combination of nivolumab with the higher dose of ipilimumab, 
which has already been demonstrated to be tolerable. 
Safety of the triplet combination in the proposed indication will be monitored continuously on a 
daily basis by the Medical Monitor, and enrollment will be staggered given the timing of 
amendment approval differ at individual sites as well as the limited number of eligible patients 
available at each site. No more than 6 patients will be enrolled in the first week of the study with 
subsequent enrollment of 6 subjects per week during the first month. A scheduled safety 
review by the Medical Monitor will occur after 12 patients are treated and have been followed 
for at least 1 month and regular safety telephone conferences will be performed with the 
investigators participating in studying the triplet combination in the proposed indication.
3.1.2
Dose-Escalating Safety Evaluation Phase for Arm N-I
The combination of 1 mg/kg nivolumab + 3 mg/kg ipilimumab is already approved for the 
treatment of advanced and metastatic melanoma regardless of BRAF mutational status and has 
more recently been tested in NSCLC and RCC. This regimen is expected to also be tolerable in 
the tumors being studied in this protocol. However, as an added safety precaution, the 
combination of N-I will first be assessed in a dose escalating safety phase. This safety evaluation 
will be conducted for each of the investigated tumor types independently (Table 3.1.2-1). 
Recently, data from Phase 1/2 studies in NSCLC and RCC have shown, that the dose level of 
1 mg/kg ipilimumab plus 3 mg/kg nivolumab is well tolerated while potentially preserving the 
tumor efficacy.9,10 Therefore, a Dose Level 2b (nivolumab 3 mg/kg, ipilimumab 1 mg/kg) will 
be investigated in the Dose-Escalating Safety Evaluation Phase in case Dose Level 2 is not 
tolerable for any of the tumor types being studied.
Table 3.1.2-1:
Dose Cohort for Arm N-I
Dose Cohort Level
Nivolumab (mg/kg)
Ipilimumab (mg/kg)
-1
0.3
1
1
1
1
2
1
3
2b
3
1
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The first dose cohort will be Level 1. If this is deemed tolerable, then Level 2 will be initiated. 
If Level 1 is not tolerable, then Level -1 will be initiated. The BC cohort will start at Level 2. 
If Dose Level 2 is not tolerable for a certain tumor type, Dose Level 2b will be investigated. 
There will be no dose escalation beyond Level 2 or Level 2b. Once the highest dose level for 
further investigation has been confirmed in the Dose-Escalating Safety Evaluation Phase, 
Arm N-I will continue enrolling with Stage 1 (Section 3.1.3).
Subjects on active treatment need to be followed up for at least 6 weeks after start of study 
treatment before determination of the tolerability of a dose level. However, tolerability beyond 
6 weeks may also be taken into consideration. The criteria for tolerability (Table 3.1.2-2) are 
based 
on 
drug 
related 
adverse 
events 
leading 
to 
permanent 
discontinuation 
(listed in Section 4.5.5) and include:

If none of the first 3 subjects in a given dose level permanently discontinue treatment due to 
study drug related adverse events within the first 6 weeks, then this dose cohort will be 
deemed as tolerable. For Dose Cohort Level 2 or Dose Cohort Level 2b, at least 6 subjects 
need to have been exposed to this dose level and followed up for at least 6 weeks after start 
of study treatment before the enrollment will proceed in Stage 1. The enrollment of these 
6 subjects will occur in a staggered mode, first 3 subjects will be enrolled and followed up 
for at least 6 weeks before the next 3 subjects will be enrolled and followed up for at least 
6 weeks.

If one or two of the first 3 subjects in a dose cohort permanently discontinue treatment within 
the first 6 weeks due to study drug related adverse events, this cohort will be expanded to 
6 subjects. 

If one of 6 subjects in a dose cohort permanently discontinue treatment due to study drug 
related adverse events within the first 6 weeks, then dose cohort will be deemed as tolerable.

If two of 6 subjects in a dose cohort permanently discontinue treatment within the first
6 weeks due to study treatment related adverse events, this cohort may be expanded to 
9 subjects. If an expansion is not possible because of the severity of the adverse events 
leading to permanent discontinuation, then this dose cohort will be deemed not tolerable.

If no more than two of 9 subjects in a dose cohort permanently discontinue treatment due to 
study treatment related adverse events within the first 6 weeks, then this dose cohort will be 
deemed as tolerable.

If at least three of the first 9 subjects in a dose cohort permanently discontinue treatment 
within the first 6 weeks due to study treatment related adverse events, a Dose -1 Cohort 
(in case of toxicities at Dose Level 1) or a Dose 2b Cohort (in case of toxicities at Dose 
Level 2) may proceed.
For the decision to enroll a Dose -1 or Dose 2b Cohort, the clinical severity of the adverse events 
leading to permanent discontinuation in the previous Dose Cohort will be taken into 
consideration.
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Table 3.1.2-2:
Dose Cohort for Arm N-I
Number of subjects treated and 
followed up for at least 6 weeks 
after start of study treatment
Number of subjects with permanent 
discontinuation due to treatment 
related adverse events
Next Step
3
0
Dose tolerable
3
1-2
Expand to 6 subjects
6
1
Dose tolerable
6
2
Expand to 9 subjects
9
2
Dose tolerable
9
3
Dose not tolerablea
a discussion with investigators to review risk/benefit taking into account reversibility of AEs and depth of response
3.1.2.1
Evaluation of Risk/Benefit for Doses that do not meet Tolerable Criteria
In the event of 3 of the first 9 subjects requiring permanent discontinuation, a discussion with 
investigators may be held to review the risk/benefit of this regimen. The rationale for this 
evaluation is that the most frequent severe drug related AEs for the combination in melanoma 
have been asymptomatic, reversible laboratory events (ie, LFTs and lipase) and there is 
preliminary evidence of deep and durable responses in the N-I arm in advanced melanoma 
(CA209004). Therefore, a discussion of the risk/benefit of the regimen will be triggered if the 
following criteria are met:

A majority of subjects who discontinue due to treatment related AEs have deep tumor 
response (ie, > 80% reduction)

All treatment related AEs leading to discontinuation are non-fatal, reversible and without 
severe sequela (ie, GI perforation)

A majority of the treatment related AEs are laboratory in nature, asymptomatic, and 
monitorable via routine blood draws
If a decision is made to continue with a regimen because of a favorable risk/benefit profile 
(ie, non-fatal AEs in subjects with near CRs that are durable) and despite meeting the ‘not 
tolerable’ criteria above, then IRBs must be notified, ICFs must be updated, and discussion of the 
risk/benefit must be documented with all future subjects who enroll on this regimen.
3.1.3
Staged Enrollment (Stage 1 and Stage 2)
3.1.3.1
Stage 1
This Stage is intended to assess the efficacy in 18 subjects per treatment arm per tumor type to 
determine whether enrollment should continue to Stage 2. For efficacy determination, each Arm 
within each tumor type will be assessed independently.
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Arm N: The enrollment and treatment of 18 subjects to Arm N per tumor type can begin while 
the initial Dose Cohort for Arm N-I in this tumor type is still ongoing. The dose level in Arm N 
is 3 mg/kg nivolumab IV every two weeks (Q2W). This dose has been established in more than 
700 subjects with various tumor types exposed to nivolumab monotherapy with a tolerable 
AE profile. Therefore no dose adjustments for Arm N are planned.
Arm N-I: Up to 18 subjects will be enrolled and treated in this arm per tumor type at the highest 
tolerated Dose Level determined during the Dose Escalating Safety Evaluation phase. 
The 3-9 subjects treated at the highest dose level confirmed for further investigation from the 
Dose Escalating Safety Evaluation phase will be counted as part of the 18 required subjects.
3.1.3.2
Criteria to proceed from Stage 1 to Stage 2
The decision to proceed from Stage 1 to Stage 2 will be made for each tumor and for each 
treatment arm independently and include (Table 3.1.3.2-1):

2 or more of 18 subjects in a given arm must have confirmed PR or CR before enrollment for 
that arm will be continued in Stage 2. The tolerability of the regimen will continue to be 
evaluated by the Sponsor with the investigators to ensure that it is acceptable for continued 
enrollment.

Subjects with initial PD per RECIST 1.1 who continue treatment in their initially 
assigned treatment arm beyond progression (Section 4.5.7) and subsequently reach 
confirmed immune related CR or PR (relative to initial tumor assessment) and including 
any new measurable lesions within the sum of all target lesions, will be considered as 
having an objective response for the purposes of meeting criteria for moving from 
Stage 1 to Stage 2. Although not standard RECIST 1.1, these immune related response 
criteria using unidimensional measurements account for the unusual immune related 
tumor response patterns reported for both ipilimumab and nivolumab.

Once the last subject in a given treatment arm has permanently discontinued treatment for 
any reason or has reached the Week 48 Tumor Assessment, and the above criteria are not 
met, then this treatment arm will not proceed to Stage 2. Ongoing subjects will continue to be 
followed up for efficacy and safety.

In case that 2 or more of subjects in a given arm enrolling in Stage 1 have confirmed PR or 
CR, but the enrollment of 18 subjects for Stage 1 has not been completed or 18 subjects have 
been enrolled but have not been randomized and started treatment at that timepoint, the 
following applies:

Arm N: the enrollment for that arm can be continued in Stage 2. The tolerability of the 
regimen will continue to be evaluated by the Sponsor with the investigators to ensure that 
it is acceptable for continued enrollment.

Arm N-I: at least 9 subjects need to have been exposed to the highest dose level which 
has been confirmed for Stage 1 and followed up for at least 6 weeks after start of study 
treatment before the enrollment for that arm can be continued in Stage 2. The tolerability 
of the regimen will continue to be evaluated by the Sponsor with the investigators to 
ensure that it is acceptable for continued enrollment.
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Table 3.1.3.2-1:
Efficacy criteria to proceed from Stage 1 to Stage 2
Efficacy criteria
Next Step
2 or more of 18* subjects in a given arm have confirmed PR or CR
Go into Stage 2
1 or no of 18* subjects in a given arm have confirmed PR or CR.
No Go into Stage 2
* see Section 3.1.3.2 last bullet point for further clarification
3.1.3.3
Stage 2
Arm N: For treatment Arm N of the given tumor type that continues to Stage 2, additional 
subjects will be assigned to a total of 40 subjects, inclusive of those enrolled in Stage 1. For 
tumor types where nivolumab monotherapy proceeded to Stage 2, assessment of Dose Level 2b 
in Stage 2 (nivolumab 3 mg/kg + ipilimumab 1 mg/kg, n=40 subjects) will be initiated for that 
tumor type. A separate evaluation of Dose Level 2b may be necessary if the safety and 
tolerability of Dose Level 2 has not been confirmed.
Arm N-I (Dose Level 2): In case treatment Arm N-I at Dose Level 2 proceeds to Stage 2, 
additional subjects will be assigned to a total of 40 subjects at Dose Level 2, inclusive of those 
enrolled in Stage 1. In order to investigate the Dose Level 2b with a potentially better tolerability 
while preserving tumor efficacy, an additional 40 subjects at Dose Level 2b will be enrolled once 
Arm N-I Dose Level 2 proceeds to Stage 2. In this case, a separate safety evaluation of Dose 
Level 2b is not necessary, as the safety and tolerability of Dose Level 2 had already been 
confirmed previously. 
Within a given tumor type, the treatment arms can proceed to Stage 2 independent of the status 
of the other treatment arm. 
For Stage 2, upon completion of enrollment of the initial 40 subjects, additional subjects may be 
assigned into Arm N and Arm N-I up to a total of 100 subjects (including those assigned in 
Stage 1) in each treatment arm of the given tumor type. For tumor types where nivolumab 
monotherapy or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg proceeded to Stage 2, assessment 
of Dose Level 2b in Stage 2 (nivolumab 3 mg/kg + ipilimumab 1 mg/kg, n=up to 70 subjects) 
may be initiated for that tumor type.
3.1.3.4
Modified Design Bladder Cancer Cohort 
Bladder arms N and N-I (Dose Levels 2 and 2b) will be conducted as a One Stage Design with 
the treatment of 26-105 subjects in each arm. The Safety Evaluation Phase for the N-I arm will 
start at Dose Level 2 (nivolumab 1 mg/kg, ipilimumab 3 mg/kg) and will evaluate safety and 
tolerability after the first 6 randomized subjects. Following the N-I safety evaluation phase, Dose 
Levels 2 will treat approximately 92 subjects and 2b will treat up to a total of 105 subjects. 
Based on the safety evaluations thus far on study, no dose escalation phase is necessary for 
bladder cohort N I Dose Level 2b (nivolumab 3 mg/kg, ipilimumab 1 mg/kg).
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3.1.3.5
Arm N-I (Dose Level 2b)
Based on the safety evaluations thus far on study, no dose escalation phase is necessary for 
bladder cohort N-I Dose Level 2b (nivolumab 3 mg/kg, ipilimumab 1 mg/kg).
3.1.4
SCLC Expansion
SCLC cohorts Arm N and Arm N-I met the pre-specified safety and efficacy criteria and 
proceeded to Stage 2. Based on an interim data review, disease control rates (SD + PR + CR) of 
36% and 57% for Arms N and N-I, respectively, were estimated. In order to further investigate 
nivolumab and nivolumab combined with ipilimumab activity in specific SCLC subpopulations, 
the SCLC expansion cohorts will enroll additional subjects based on response to prior treatment 
and the number of previous therapies. Up to 250 second or third line subjects will be randomized
in a 3:2 ratio to one of 2 expansion groups: Arm A (150 subjects treated with nivolumab 3 mg/kg 
every 2 weeks (Q2W)) or Arm B (100 subjects treated with nivolumab 1 mg/kg + ipilimumab 3 
mg/kg every 3 weeks (Q3W) for 4 cycles followed by nivolumab 3 mg/kg (Q2W) and will be 
stratified for number of prior treatment lines (1 vs 2 prior chemotherapy regimens).
The study population for the SCLC expansion cohort is specified as follows:

Histopathologically or cytologically confirmed diagnosis of SCLC.

All subjects had platinum-based first-line treatment. Subjects with previous second-line 
chemotherapy treatment are eligible as well.

Subjects with platinum refractory, resistant, or sensitive disease are eligible.

Subjects with initial diagnosis of limited or extensive disease are eligible.

Documented objective radiographic disease progression at study entry.
Tumor assessments for subjects in the SCLC expansion cohort will undergo a BICR assessment.
The crossover option refers only to the original cohorts and not the new cohorts enrolled under or 
after Amendment 09.
3.1.5
Duration of Study Treatment
The study treatment will be continued until disease progression (investigator-assessed 
RECIST 1.1-defined progression) or occurrence of unacceptable toxicity as defined in 
Section 4.5.5. For subjects achieving confirmed CR or a PR for more than 3 months (long lasting 
PR) the investigator may decide to hold treatment for this subject after discussion with the 
medical monitor of the sponsor. During the treatment hold subjects should follow all study 
procedures as specified in Section 5.1. Subjects for which treatment was held following long 
lasting responses and who experience a recurrence of disease progression may reinitiate their last 
study treatment. Before reinitiating treatment, the investigator should discuss the individual case 
with the medical monitor and document in the study records.
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3.1.6
Crossover for Subjects in Arm N
Subjects in Arm N may crossover to Arm N-I if all of the following criteria are met:

The Safety Evaluation Phase for the N-I regimen has been completed and at least 6 subjects 
have been exposed to the dose level used for Stage 1 of the N-I regimen. In case 
Dose Level 2b has been activated and completed the safety assessment, subjects for cross 
over will be assigned to Dose Level 2 or Dose Level 2b after discussion between the sponsor 
and investigator taking into consideration previous safety and efficacy signals at these dose 
levels and the status of the individual subject planned for cross over.

Subject has further disease progression (investigator-assessed RECIST 1.1-defined 
progression according to description provided in Section 4.5.7, confirmed at least 4 weeks 
after the initial tumor assessment showing progression (definition of confirmed progression
see Appendix 3)) in the absence of clinical deterioration. For subjects with clear evidence of 
new or progressing brain metastases a confirmation is not required. These subjects may 
proceed with brain radiation therapy and, if necessary, with gamma-knife or surgical 
resection, after having completed the therapy a cross over to Arm N-I can be considered 
(see Section 3.4.2.1).

Subjects with rapidly progressing tumors under nivolumab monotherapy may undergo 
radiation treatment first before initiation of the cross over after discussion between the 
sponsor and investigator.

Subject has not experienced nivolumab related adverse events leading to permanent 
discontinuation as described in Section 4.5.5.

Subject is not continuing to derive any clinical benefit from nivolumab single agent therapy 
as assessed by the investigator which would allow continuation of nivolumab monotherapy 
(see Section 4.5.8).

Subject is not a SCLC patient enrolled based on the Amendment 09 expansion.

The individual case must be discussed with the medical monitor prior to cross over.
Subjects crossing over to Arm N-I will start treatment at Day 1 Week 1 as described for subjects 
originally randomized to Arm N-I. Subjects who crossed over and subsequently have an 
objective response in Arm N-I will not be considered in the decision making for Arm N-I 
proceeding to Stage 2. Subjects in Arm N-I cannot crossover to Arm N.
3.1.7
Re-exposure with Nivolumab/Ipilimumab for Subjects in Arm N-I
Subjects in Arm N-I may undergo a re-exposure with nivolumab/ipilimumab if they achieved an 
initial objective response (PR or CR) or stable disease of 3 months and had a subsequent 
documented progression. Subjects must fulfill the following criteria:

Subjects have not experienced any related adverse events as described in Section 4.5.5
(discontinuation criteria).

Eligible subjects will receive up to four doses of nivolumab/ipilimumab (based on treatment 
assigned at randomization) during Re-exposure.
Subjects can receive nivolumab 
monotherapy, if ipilimumab caused toxicities leading to its discontinuation (section 4.5.5)
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
Dosing may be delayed for toxicity (see Section 4.5.2).

Subjects who have permanently discontinued study therapy for any reason and are in the 
follow up phase may not receive any re-exposure dosing.
3.1.8
Review of Safety
The subjects’ safety will be monitored on an ongoing basis as described fully in Section 7. Safety 
conference calls with investigators and representatives of the sponsor will be held approximately 
every other week with additional meetings as necessary. Decisions for the safety evaluation 
phase of Arm N-I and for continuing from Stage 1 to Stage 2 in both treatment arms will be 
made in conjunction with the investigators. In addition, a BMS medical safety team (MST) 
routinely reviews safety signals across the entire nivolumab program including combination 
studies with ipilimumab.
3.1.9
Treatment Beyond Progression
Treatment beyond investigator-assessed RECIST 1.1-defined progression will be permitted if the 
subject experiences investigator-assessed clinical benefit and the subject is tolerating the study 
treatment (Section 4.5.7). No treatment beyond progression with cobimetinib is permitted.
3.1.10
Intrapatient Dose Reductions for Nivolumab, Ipilimumab and/or
Cobimetinib
Intrapatient dose reduction for nivolumab and/or ipilimumab is not permitted for any reason. 
Dose delays for the management of study treatment related adverse events are described in
Section 4.5.2.
Intrapatient dose reductions for cobimetinib should be undertaken as presented in Table 3.1.10-1
and based on the prescribing information.57
Table 3.1.10-1:
Recommended Dose Reductions for COTELLIC (Cobimetinib)
First Dose Reduction
40 mg orally once daily
Second Dose Reduction
20 mg orally once daily
Subsequent Modifications
Permanently discontinue cobimetinib if unable to 
tolerate 20 mg once daily
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3.1.11
Mandatory Availability of Tumor Material
Tumor tissue from fresh tumor biopsies must be submitted prior to treatment for retrospective 
biomarker analyses. Tumor biopsies may be done during the screening period prior to study 
treatment start. Tumor material from biopsies done before the screening period is acceptable if 
the biopsy was performed within 3 months prior to the planned treatment start and no other 
systemic cancer therapy was administered in the meanwhile. Baseline tumor biopsies should 
preferably be performed from a tumor site that is NOT the only site of measurable disease. For 
subjects with only one site of measurable disease, tumor biopsies from this one tumor site are 
allowed if at least one of the following criteria is met:
-
CT imaging performed after biopsy and there is still measurable disease or
-
The type of biopsy is not expected to impact the measurability (eg, core needle biopsy) 
regardless on when imaging occurred, prior to or after biopsy.
3.1.12
Study Phases
This study will consist of three phases: screening, treatment, and follow-up.
Screening Phase:

Begins by establishing the subject’s initial eligibility and signing of the informed consent 
form (ICF).

Subject is enrolled using the Interactive Voice Response System (IVRS).
Treatment Phase:

Begins with the vial assignment call to the IVRS.

A negative pregnancy test must be documented within 24 hours prior to the start of 
investigational product.

Within 3 days from treatment assignment, the subject must receive the first dose of study 
medication:

Arm N (nivolumab monotherapy):
Nivolumab 3 mg/kg IV every two weeks (Q2W). See Table 4.5-1

Arm N-I (nivolumab + ipilimumab)
Dose Escalation Phase:
Staged Enrollment Phase: Dose Level determined in Dose Escalation Phase. See Table 4.5-2 and 
Table 4.5-3.

Dose Level 1, Nivolumab 1 mg/kg IV combined with ipilimumab 1 mg/kg IV Q3W for 
4 doses, then nivolumab 3 mg/kg IV Q2W. See Table 4.5-2 and Table 4.5-3.

Dose Level 2: Nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV Q3W for 4 
doses, then nivolumab 3 mg/kg IV Q2W.
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
Dose Level 2b: Nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV Q3W for 4 
doses, then nivolumab 3 mg/kg IV Q2W.

Dose Level 2c: Nivolumab 3 mg/kg IV Q2W combined with ipilimumab 1 mg/kg Q6W.

Dose Level 2d: Nivolumab 3 mg/kg IV Q2W combined with ipilimumab 1 mg/kg Q6W + 
cobimetinib 60 mg per os qd 21 days on/7 days off for the additional pancreatic cancer cohort 
only.

Adverse event assessments will be documented at each visit throughout the study.
On-study laboratory assessments (after D1W1) should be drawn within 72 hours prior to dosing 
according to the schedule in Table 5.1-2, Table 5.1-3, Table 5.1-4, and Table 5.1-5.

Women of child bearing potential (WOCBP) must have a negative pregnancy test 
documented as follows:

Arm N and Arm N-I2c: before every other nivolumab administration, within 24 hours 
prior to dosing.

Arm N-I: before every combined nivolumab / ipilimumab administration, within 24 hours 
prior to dosing. Thereafter every 4 weeks, within 24 hours prior to nivolumab dosing.

PK samples and immunogenicity samples will be collected according to the schedule in
Section 5.5.

Study drug dosing may be delayed for toxicity. See Section 4.5.2.

Treated subjects will be evaluated for response according to the RECIST 1.1 guidelines 
beginning 6 weeks (1 week) after first dose and continuing every 6 weeks (1 week) for 
the first 24 weeks, and then every 12 weeks (1 week) while on treatment or on treatment 
hold for any reason until disease progression (investigator-assessed RECIST 1.1-defined 
progression) or treatment discontinuation, except for subjects treated beyond progression or 
who discontinued treatment for other reasons than PD.
This phase ends when the subject is discontinued from study therapy. For a complete list of 
reasons for treatment discontinuation, see Section 4.5.5.
Follow-Up Phase

Begins when the decision to discontinue a subject from study therapy is made 
(no further treatment with study therapy).
Two follow-up visits include collection of PK/immunogenicity samples Table 5.1-7, Table 5.5.1-
1, and Table 5.5.1-2.

Subjects who discontinue treatment for reasons other than tumor progression will continue to 
have tumor assessments beginning 6 weeks (1week) after first dose and continuing every 
6 weeks (1 week) for the first 24 weeks from first dose, and every 12 weeks (1 week) 
thereafter until disease progression (investigator-assessed RECIST 1.1-defined progression).
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This does also apply to subjects whose treatment was put on hold after achieving confirmed 
CR or PR for more than 3 month (long lasting PR).

Subjects will be followed for drug-related toxicities until these toxicities resolve, return to 
baseline or are deemed irreversible. All adverse events will be documented for a minimum of 
100 days after last dose.

Follow up visits should be made in-person. If a subject is unable to make an in-person visit, 
the reason should be clearly documented at the site.

Follow-up visit 1 (FU1) = 35 days from the last dose 7 days or coincide with the date of 
discontinuation (7 days) if date of discontinuation is greater than 42 days after last dose, 
Follow-up visit 2 (FU2) = 80 days (7 days) from follow-up visit 1.

After completion of the first two follow-up visits, subjects will be followed every 3 months 
for survival via in-person visits, phone or email. Ad hoc survival data requests may be made 
during the study as well, particularly during database locks.
3.1.13
Total Study Duration
It is projected that the accrual for the Initial Dose Cohort and the Efficacy Signal Detection -
Stage 1 of the study will be completed within 4 months after FPFV and that the results of the 
interim analysis will be available 9 months after FPFV. The final analysis is expected at 
60 months after FPFV. The total study duration is not expected to be affected by the 
implementation of the additional pancreatic cancer cohort.
3.2
Post Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive study drug. Study drug will be provided via an extension of the study, a 
rollover study requiring approval by responsible health authority and ethics committee or 
through another mechanism at the discretion of BMS. BMS reserves the right to terminate access 
to study drug if any of the following occur: a) the marketing application is rejected by 
responsible health authority; b) the study is terminated due to safety concerns; c) the subject can 
obtain medication used in this study as study treatment from a government sponsored or private 
health program; or d) therapeutic alternatives become available in the local market.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed consent 
form in accordance with regulatory and institutional guidelines. This must be obtained
before the performance of any protocol related procedures that are not part of normal 
subject care
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests, fresh tumor biopsies, and other requirements of the study.
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2. Target Population
a) Subjects with pathologically confirmed locally advanced or metastatic disease of the 
following tumor types:
i)
Women with histologically or cytologically confirmed breast carcinoma who must 
meet all of the following:
(1) Tumor must be “triple receptor negative” defined as ER/PR negative per local lab 
and HER-2 negative defined as HER-2 0 or 1+ by IHC, or IHC 2+ and ISH not 
amplified, or ISH-non amplified.
AND
(2) Subjects must have progression or refractory disease. Subjects must have had at 
least 1 chemotherapy regimen for the treatment of metastatic (Stage IV) or locally 
advanced disease.
OR
(3) Subject actively refuses chemotherapy for the treatment of metastatic (Stage IV) 
or locally advanced disease considered as standard treatment for this disease 
stage, despite being informed by the investigator about the treatment options. 
Subjects actively refusing chemotherapy must have had progression or refractory 
disease prior to starting study treatment. The subject’s refusal must be thoroughly 
documented. The investigator will discuss each individual subject refusing 
chemotherapy with the sponsor’s medical monitor to confirm eligibility.
ii) Subjects with histologically confirmed Gastric or Gastro-Esophageal Junction 
Carcinoma (including adenocarcinoma arising from the lower esophagus) who must 
meet all of the following:
(1) Subjects must have progression or refractory disease. Subjects must have had at 
least 1 chemotherapy regimen for the treatment of metastatic (Stage IV) or locally 
advanced disease. Subjects with HER-2 positive tumors must have had previous 
treatment with trastuzumab.
OR
(2) Subject actively refuses chemotherapy or biological therapy for the treatment of 
metastatic (Stage IV) or locally advanced disease considered as standard 
treatment for this disease stage, despite being informed by the investigator about 
the treatment options. Subjects actively refusing chemotherapy must have had 
progression or refractory disease prior to starting study treatment. The subject’s 
refusal must be thoroughly documented. The investigator will discuss each 
individual subject refusing chemotherapy with the sponsor’s medical monitor to 
confirm eligibility.
iii) Subjects with histologically confirmed Pancreatic adenocarcinoma who must meet all 
of the following (Not applicable per Amendment 13):
(1) Subjects must not have clinically relevant ascites at baseline, such as ascites in 
need of paracentesis.
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AND
(2) Subjects must have had best response of stable disease, or progression or 
refractory disease during or after at least 1 chemotherapy regimen for the 
treatment of metastatic (Stage IV) or locally advanced disease 
OR
(3) Subject actively refuses chemotherapy for the treatment of metastatic (Stage IV) 
or locally advanced disease considered as standard treatment for this disease 
stage, despite being informed by the investigator about the treatment options. 
Subjects actively refusing chemotherapy must have had best response of stable 
disease, or progression or refractory disease prior to starting study treatment. The 
subject’s refusal must be thoroughly documented. The investigator will discuss 
each individual subject refusing chemotherapy with the sponsor’s medical 
monitor to confirm eligibility.
iv) Subjects with histologically or cytologically confirmed small cell lung cancer. 
Subjects must have progression or refractory disease. Subjects must have had at least 
1 platinum based chemotherapy regimen for the treatment of limited or extensive 
stage disease, but not more than 2 prior chemotherapy regimens. For subjects to be 
enrolled in the SCLC expansion cohorts to following eligibility criteria apply:
(1) All subjects must have had platinum-based first-line treatment. Subjects with 
previous second-line chemotherapy treatment are eligible as well.
(2) Subjects with platinum refractory, resistant, or sensitive disease are eligible 
(Appendix 4).
(3) Subjects with initial diagnosis of limited or extensive disease are eligible.
(4) Documented objective radiographic disease progression at study entry.
v) Subjects with histologically or cytologically confirmed urothelial
carcinoma 
(including mixed histologies of urothelial carcinoma with elements of other subtypes) 
of the renal pelvis, ureter, bladder, or urethra, who must meet all of the following:
(1) Subjects must have progression or refractory disease. Subjects must have had at 
least 1 platinum based chemotherapy regimen for the treatment of metastatic 
(Stage IV) or locally advanced unresectable disease.
OR
(2) Subjects with disease recurrence within 1 year of completing a platinum based 
neoadjuvant or adjuvant therapy.
OR
(3) Subject actively refuses chemotherapy for the treatment of metastatic (Stage IV) 
or locally advanced unresectable disease considered as standard treatment for this 
disease stage, despite being informed by the investigator about the treatment 
options. Subjects actively refusing chemotherapy must have had progression or 
refractory disease prior to starting study treatment. The subject’s refusal must be 
thoroughly documented. The investigator will discuss each individual subject 
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refusing chemotherapy with the sponsor’s medical monitor to confirm eligibility.
NA for subject enrolling per protocol amendment 16.
AND
(4) Metastatic or surgically unresectable (cT4b, or any N+ [N1-3], or any M-1) 
disease.
vi) Subjects with histologically confirmed ovarian carcinoma (including epithelial 
ovarian cancer (OC), primary peritoneal, or fallopian tube carcinoma) who must meet 
all of the following: 
(1) Subjects must have received one platinum-based chemotherapeutic
regimen for management of primary disease, possibly including 
intraperitoneal therapy, consolidation, biologic/targeted (non-cytotoxic) 
agents (eg, bevacizumab) or extended therapy administered after surgical 
or non-surgical assessment. Subjects are allowed to have received, but are 
not required to have received subsequent cytotoxic regimens for 
management of recurrent or persistent disease. For the purposes of this 
study, PARP inhibitors given for recurrent or progressive disease will be 
considered cytotoxic. A line of therapy is defined as a regimen used to 
treat initial disease (frontline) or following disease progression (second 
and subsequent lines). A change in regimen for reasons of toxicity or 
consolidation/maintenance in the absence of disease progression does not 
constitute a new line of therapy.
(2) Subjects must have documented disease progression after completion of 
their most recent regimen.
(3) Subjects with platinum refractory, resistant, or sensitive disease are 
eligible (Appendix 5).
vii)Additional pancreatic cancer cohort: Subjects with histologically confirmed 
pancreatic adenocarcinoma who must meet all of the following:
(1) Subjects must not have clinically relevant ascites at baseline, such as ascites in 
need of paracentesis.
AND
(2) Treatment with at least one, but not more than 2 previous lines of chemotherapy 
in the metastatic/advanced setting.
(3) Documented objective radiographic disease progression at study entry.
(4) Royal Marsden score 0 or 1 (Appendix 6) 94
OR
(5) Subject actively refuses chemotherapy for the treatment of metastatic (Stage IV) 
or locally advanced disease considered as standard treatment for this disease 
stage, despite being informed by the investigator about the treatment options. 
Subjects actively refusing chemotherapy must have had best response of stable 
disease, or progression or refractory disease prior to starting study treatment. The 
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subject’s refusal must be thoroughly documented. The investigator will discuss 
each individual subject refusing chemotherapy with the sponsor’s medical 
monitor to confirm eligibility.
A line of therapy is defined as a regimen used to treat initial disease (frontline) 
or following disease progression (second and subsequent lines). A change in 
regimen for reasons of toxicity or consolidation/maintenance in the absence of 
disease progression does not constitute a new line of therapy.
b) Subjects must have measurable disease by CT or MRI per RECIST 1.1 criteria 
(see Appendix 3). (Radiographic tumor assessment must be performed within 28 days 
prior to first dose).
c) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
(refer to Appendix 1).
d) Subjects must consent to allow for a baseline tumor biopsy. Baseline tumor biopsies 
should preferably be performed from a tumor site that is NOT the only site of measurable 
disease. For subjects with only one site of measurable disease, tumor biopsies are allowed 
if at least one of the following criteria is met:
-
CT imaging performed after biopsy and there is still measurable disease or
-
The type of biopsy is not expected to impact the measurability (eg, core needle 
biopsy) regardless on when imaging occurred, prior to or after biopsy.
Tumor material from biopsies done before the screening period is acceptable if the biopsy 
was performed within 3 months prior to the planned treatment start and no other systemic 
cancer therapy was administered in the meanwhile.
e) All baseline laboratory requirements will be assessed and should be obtained within 
14 days of first dose. Screening laboratory values must meet the following criteria:
i)
WBCs 
2000/µL
ii)
Neutrophils 
1500/µL
iii) Platelets 
100 x 10³/µL
iv) Hemoglobin 
9.0 g/dL
v)
Serum creatinine 1.5 x ULN or calculated creatinine clearance (CrCl) 
40 mL/minute (using Cockcroft/Gault formula)
Female CrCl = (140- age in years) x weight in kg x 0.85
                                   72 x serum creatinine in mg/ dL
Male CrCl = (140- age in years) x weight in kg x 1.00
                                      72 x serum creatinine in mg/ dL
vi) AST 
3 x ULN 
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vii) ALT 
3 x ULN 
viii) Total Bilirubin
1.5 x ULN (except subjects with Gilbert Syndrome who can have 
total bilirubin < 3.0 mg/dL)
ix) Albumin 3 g/dL
x)
Lipase 1.5 ULN. Subjects with Lipase > 1.5 ULN may enroll if there are neither 
clinical nor radiographic signs of a pancreatitis.
xi) Amylase 1.5 ULN. Subjects with Amylase > 1.5 ULN may enroll if there are 
neither clinical nor radiographic signs of a pancreatitis.
f)
Prior focal radiotherapy to an isolated bony or soft tissue metastasis must be completed at 
least 2 weeks before study drug administration. 
g) Subject Re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been assigned / has 
not been treated). If re-enrolled, the subject must be re-consented and assigned a new 
subject number from IVRS.
3. Age and Reproductive Status
a) Men and women 18 years of age
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
24 hours prior to the start of study drug.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception from the time 
of enrollment for the duration of treatment with study drug (s) plus approximately 5 half-
lives of study drug (s) plus 30 days (duration of ovulatory cycle) for a total of 5 months
post treatment completion.
e) Men who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug (s) plus 
approximately 5 half-lives of study drug (s) plus 90 days (duration of sperm turnover) for 
a total of 7 months post-treatment completion.
f)
Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However WOCBP must still undergo 
pregnancy testing as described in these sections.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% per year when used consistently and correctly.
At a minimum, subjects must agree to use one highly effective method of contraception. See 
Appendix 7 for details on highly effective methods of contraception.
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3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are 
eligible if these have been treated and there is no magnetic resonance imaging (MRI) 
evidence of progression for at least 4 weeks after treatment is complete and within 
28 days prior to first dose of study drug administration. There must also be no 
requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day 
prednisone equivalents) for at least 2 weeks prior to study drug administration. Subjects 
with incidental findings of asymptomatic brain metastases at screening may start study 
treatment without prior radiation treatment after discussion between the sponsor and 
investigator.
2. Medical History and Concurrent Diseases
a) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may 
increase the risk associated with study participation or study drug administration, impair 
the ability of the subject to receive protocol therapy, or interfere with the interpretation of 
study results.
b) Other prior malignancy active within the previous 3 years except for local or organ 
confined early stage cancer that has been definitively treated with curative intent, does 
not require ongoing treatment, has no evidence of residual active disease, and has a 
negligible risk of recurrence and is therefore unlikely to interfere with the primary and 
secondary endpoints of the study, including response rate and safety.
c) Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, 
type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only 
requiring hormone replacement, or conditions not expected to recur in the absence of an 
external trigger are permitted to enroll.
d) Subjects with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 days of first dose. Inhaled or topical steroids, and adrenal replacement steroid doses 
are permitted in the absence of active autoimmune disease.
e) Prior therapy with experimental anti-tumor vaccines; any T cell co-stimulation or 
checkpoint pathways, such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-CTLA-4 antibody, including ipilimumab; or other medicines specifically targeting 
T cell is also prohibited.
f)
All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must 
have resolved to grade 1 (NCI CTCAE version 4) or baseline before administration of 
study drug. Subjects with toxicities attributed to prior anti-cancer therapy which are not 
expected to resolve and result in long lasting sequelae, such as neuropathy after 
platinum-based therapy, are permitted to enroll.
g) Treatment with any chemotherapy, radiation therapy, biologics for cancer, or 
investigational therapy within 28 days of first administration of study treatment (subjects 
with prior cytotoxic or investigational products < 4 weeks prior to treatment might be 
eligible after discussion between investigator and sponsor, if toxicities from the prior 
treatment have been resolved to CTC grade 1 level). 
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h) Subjects which have been previously enrolled and randomized in Studies BMS 
CA209331 or BMS CA209451 are not eligible.
i)
Inability to take oral medication or significant nausea and vomiting, malabsorption, 
external biliary shunt, significant bowel resection that would preclude adequate 
absorption of oral medication for subjects in the additional pancreatic cancer cohort only.
3. Physical and Laboratory Test Findings
a) Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBV sAg) test or 
positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV 
antibody test indicating acute or chronic infection.
b) Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be 
performed at sites where mandated locally.
c) Subjects must not be dependent on continuous supplemental oxygen use.
d) For subjects assigned to the additional pancreatic cancer cohort: baseline echocardiogram 
showing left ventricular ejection fraction (LVEF) below the institutional lower limit of 
normal (LLN) or < 50%, whichever is lower, and electrocardiogram with corrected 
QT 450 ms should be excluded.
4. Allergies and Adverse Drug Reaction
a) History of allergy to study drug components.
b) History of severe hypersensitivity reaction to any monoclonal antibody.
5. Sex and Reproductive Status
a) WOCBP who are pregnant or breastfeeding.
b) Women with a positive pregnancy test at enrollment or prior to administration of study 
medication.
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 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In 
addition, women under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level > 40 mIU/mL to confirm menopause.*
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Supportive care for disease-related symptoms may be offered to all subjects on the trial.
3.4.2
Other Restrictions and Precautions
It is the local imaging facility’s responsibility to determine, based on subject attributes 
(eg, allergy history, diabetic history and renal status), the appropriate imaging modality and 
contrast regimen for each subject. Imaging contraindications and contrast risks should be 
considered in this assessment. Subjects with renal insufficiency should be assessed as to whether 
or not they should receive contrast and if so, what type and dose of contrast is appropriate. 
Specific to MRI, subjects with severe renal insufficiency (ie, estimated glomerular filtration rate 
(eGFR) < 30 mL/min/1.73m2) are at increased risk of nephrogenic systemic fibrosis. MRI 
contrast should not be given to this subject population. In addition, subjects are excluded from 
MRI if they have tattoos, metallic implants, pacemakers, etc.   
The ultimate decision to perform MRI in an individual subject in this study rests with the site 
radiologist, the investigator and the standard set by the local Ethics Committee.
3.4.2.1
Palliative Radiation Therapy
Palliative (limited-field) radiation therapy is permitted for pain control to sites of bone disease or 
other non-target lesions present at baseline or new lesions. For subjects with new or progressing 
brain metastases or other lesions, except SCLC subjects from the expansion cohorts under or 
after Amendment 09, radiation therapy is permitted before a crossover to Arm N-I can be 
considered.
1) Bone and other metastases
a) For bone or other disease sites present at baseline or new, the lesion being considered for 
palliative radiation is not a target lesion.
b) The case is discussed with the BMS medical monitor, and the medical monitor agrees 
that the conditions required to receive palliative radiation are met.
2) Brain metastases or other lesions
a) Subject is enrolled in the nivolumab monotherapy arm.
b) The case is discussed with the BMS medical monitor, and the medical monitor agrees 
that the conditions required to receive palliative radiation are met.
c) After completion of the brain or other lesions radiation therapy, the BMS Medical 
Monitor must be consulted before a crossover to Arm N-I can be permitted. Treatment in 
the crossover arm can only be started after there is no MRI evidence of progression for at 
least 2 weeks after brain radiation treatment is complete.
3.4.2.2
Surgical Resection or Stereotactic Radiotherapy Following Initial 
Response or Long-Term Stable Disease
Investigators may choose to resect solitary lesions in subjects with residual or new disease 
following initial response or stable disease of > 3 months (long-term stable disease) and render 
the subject free of macroscopic disease. Subjects enrolled in this study may have lesions treated 
surgically or by stereotactic radiotherapy only following consultation with the Medical Monitor 
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3.5
Discontinuation of Subjects from Treatment
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject
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
Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness

Additional protocol specified reasons for discontinuation (see Section 4.5.5).
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
All subjects who discontinue investigational product should comply with protocol specified 
follow-up procedures as outlined in Section 5. The only exception to this requirement is when a 
subject withdraws consent for all study procedures including post-treatment study follow-up or 
loses the ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment 
of either a psychiatric or physical illness).
If study 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.
For subjects achieving confirmed CR or a PR for more than 3 month (long lasting PR) the 
investigator may decide to hold treatment for this subject after discussion with the medical 
monitor of the sponsor. Subjects for which treatment was held following long lasting responses 
and who experience a recurrence of disease progression may reinitiate their last study treatment. 
Before reinitiating treatment, the investigator should discuss the individual case with the medical 
monitor and document in the study records.
3.6
Post Treatment Study Follow up
In this study, objective response rate is a key endpoint of the study. Tumor responses initiated by 
immunotherapy with nivolumab, nivolumab combined with ipilimumab, or nivolumab combined 
with ipilimumab and cobimetinib may evolve after treatment discontinuation. Therefore, post 
treatment study follow-up is of critical importance and is essential to preserving subject safety 
and the integrity of the study. Subjects who discontinue study treatment must continue to be 
followed for collection of outcome and/or survival follow-up data as required and in line with 
Section 5 until death or the conclusion of the study.
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 
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to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In 
the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, in order to obtain updated contact information. If after all 
attempts, the subject remains lost to follow-up, then the last known alive date as determined by 
the investigator should be reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drugs include both Non-investigational (NIMP) and Investigational Medicinal Products 
(IMP) and can consist of the following:

All products being tested or used as a comparator in a clinical trial. 

Study required premedication, and 

Other drugs administered as part of the study that are critical to claims of efficacy 
(eg, background therapy, rescue medications)

Diagnostic agents: (such as glucose for glucose challenge) given as part of the protocol 
requirements must also be included in the dosing data collection.
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4.1
Investigational Product
Table 4.1-1:
Product Description: Treatment Period
Product Description and 
Dosage Form
Potency
Primary Packaging
(Volume)/ Label Type
Secondary Packaging
(Qty) /Label Type
Appearance
Storage Conditions
(per label)
BMS-936558-01 Solution 
for Injectiona
100 mg 
(10 mg/mL)
10 mL per vial/ 
Open-label
10 vials per carton/ 
Open-label
Clear to opalescent 
colorless to pale yellow 
liquid. May contain 
particles
2 to 8°C. Protect from 
light and freezing
Ipilimumab Solution for 
Injection
200 mg 
(5 mg/mL)
40 mL per 
vial/Open-label
4 vials per carton/Open-
label
Clear, colorless to pale 
yellow liquid. May 
contain particles
2 to 8°C. Protect from 
light and freezing
Cobimetinib tablet
20 mg
63 tablets per bottle
n/a
White, round, film-
coated, debossed on one 
side with “COB”
15-30°C
a Nivolumab is labeled as BMS-936558-01 Solution for Injection
Premedications or medications used to treat infusion-related reactions should be sourced by the investigative sites if available and 
permitted by local regulations.
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An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational product(s) is/are: BMS-936558 (nivolumab), ipilimumab, and 
cobimetinib.
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products. 
In this protocol, non-investigational product(s) is/are: Not Applicable 
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Investigational product documentation must be maintained that includes all processes required to 
ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets).
For non-investigational product, if marketed product is utilized, it should be stored in accordance 
with the package insert, summary of product characteristics (SmPC), or similar.
Please refer to the current version of the Investigator Brochure, pharmacy reference sheets or 
pharmacy manual for complete storage, handling, dispensing, and infusion information for 
BMS-936558 (nivolumab) and ipilimumab. Please refer to the current version of the Prescribing 
Information for Cotellic (cobimetinib) for complete storage, handling, dispensing, and 
administration information.57
4.3.1
BMS-936558 (Nivolumab)
BMS-936558 (nivolumab) vials must be stored at a temperature of 2°C to 8°C and should be 
protected from light, freezing and shaking. 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.
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For details on prepared drug storage and use time of nivolumab under room temperature/light 
and refrigeration, please refer to the BMS-936558 (nivolumab) Investigator Brochure 
sections 3.2.2 and 3.2.3 and/or pharmacy reference sheets.
Nivolumab injection is to be administered as a 60-minute IV infusion in Arm N, Arms N-I, dose 
levels 1, 2, 2b, and 2c. Nivolumab injection is to be administered as a 30-minute IV infusion in 
Arm N-I, dose level 2d. During drug product preparation and handling, vigorous mixing or 
shaking is to be avoided. Care must be taken to assure sterility of the prepared solution as the 
product does not contain any antimicrobial preservative or bacteriostatic agent. Please refer to 
the nivolumab IB and/or pharmacy reference sheets for further details regarding 
preparation/administration.
4.3.2
Ipilimumab
Ipilimumab injection can be used for IV administration without dilution after transferring to a 
PVC (polyvinyl chloride), non-PVC/non-DEHP (di-(2-ethylhexyl)phthalate) or glass containers 
and is stable for 24 hours at 2-8ºC or room temperature/room light (RT/RL). For additional 
ipilimumab storage instructions, please refer to the ipilimumab IB and/or pharmacy reference 
sheets.
Recommended safety measures for preparation and handling include protective clothing, gloves, 
and safety cabinets.
Ipilimumab is to be administered as a 90-minute IV infusion in Arm N, Arms N-I, dose levels 1, 
2, 2b, and 2c. Ipilimumab is to be administered as a 30-minute IV infusion in Arm N-I, dose 
level 2d. 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 
and/or 
pharmacy 
reference 
sheets 
for 
further 
details 
regarding 
preparation/administration.
4.3.3
Nivolumab and Ipilimumab Combination
When both BMS-936558 (nivolumab) and ipilimumab 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.
4.3.4
COTELLIC (Cobimetinib)
The recommended dose of cobimetinib is 60 mg (three 20 mg tablets) orally taken once daily for 
the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. No 
treatment beyond progression with this compound is permitted.
4.4
Method of Assigning Subject Identification
The subject number will be assigned through an interactive voice response system (IVRS) once 
the subject has signed the informed consent form and is registered. Every subject that signs the 
informed consent form must be assigned a subject number in IVRS. Specific instructions for 
using IVRS will be provided to the investigational site in a separate document.
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The investigator or designee will register the subject for enrollment by following the enrollment 
procedures established by BMS. The following information is required for enrollment:

Date that informed consent was obtained

Date of birth

Gender at birth
Once enrolled in IVRS, enrolled subjects that have met all eligibility criteria will be ready for 
treatment assignment and drug vial assignment through the IVRS. The following information is 
required for drug vial assignment and randomization:

Subject number

Date of birth

Tumor Type

Date tumor tissue sample was shipped to central lab
Subjects meeting all eligibility criteria will be assigned to Arm N (nivolumab), Arm N-I 
(nivolumab + ipilimumab), Arm N-I Dose level 2b (nivolumab 3 mg/kg + ipilimumab 1 mg/kg),
Arm N-I Dose level 2c (nivolumab 3 mg/kg every 2 weeks + ipilimumab 1 mg/kg every 6 
weeks), or Arm N-I Dose level 2d (nivolumab 3 mg every 2 weeks + ipilimumab 1 mg/kg every 
6 weeks) combined with cobimetinib 60 mg orally qd 21 days on/7 days off, according to their 
tumor type and treatment arm availability:

Within a given tumor type, subjects will be assigned to a treatment arm (N or N-I Dose 
Level 2 or N-I Dose Level 2b) in a 1:1:1 ratio guided by randomization schedule if all arms 
are open.

The computer-generated randomization schemas will be prepared by a Randomization 
Coordinator within the Drug Supply Management Department of BMS Research and 
Development.

If only one or two treatment arms are open for enrollment (ie., when enrollment in Arm N-I 
is paused for an interim safety assessment, or when either arm is paused for decision making 
to proceed from Stage 1 to Stage 2 in the Efficacy Signal Detection part), then all newly to be 
assigned subjects will go into the remaining open arm(s).

Once the subject has a treatment assignment, study treatment should be initiated within 
3 working days.

Specific instructions (including an enrollment worksheet) for central enrollment and 
treatment assignment procedure will be provided to the site.
Subjects to be enrolled in the SCLC expansion cohort will be randomized in a 3:2 ratio to one of 
2 expansion groups: Arm A (150 subjects, nivolumab 3 mg/kg every 2 weeks (Q2W) or Arm B 
(100 subjects, nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks (Q3W) for 4 cycles 
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followed by nivolumab 3 mg/kg Q2W) and will be stratified for number of prior treatment lines 
(1 vs 2 prior chemotherapy regimens).
Subjects to be enrolled in the OC expansion cohort will be randomized in a 1:1:1 ratio to one of 
3 dose level groups:

Arm A (40 subjects, nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks (Q3W) for 
4 cycles followed by nivolumab 3 mg/kg Q2W)

Arm B (40 subjects, nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks (Q3W) for 
4 cycles followed by nivolumab 3 mg/kg Q2W)

Arm C (40 subjects, Nivolumab (3 mg/kg) Q2W + ipilimumab (1 mg/kg) Q6W)
Subjects to be enrolled in the PC additional cohort will be assigned to one regimen consisting of 
nivolumab 3 mg/kg Q2W + ipilimumab (1 mg/kg) Q6W + cobimetinib 60 mg orally QD 21 days 
on/7 days off.
4.5
Selection and Timing of Dose for Each Subject
The dosing regimen and schedule for Arm N, Arm N-I Dose Level -1, Dose Level 1, Dose 
Level 2, Dose Level 2b, and Dose Level 2c are detailed in Table 4.5-1 (Arm N), Table 4.5-2
(N-I Arms -1, 1, 2, and 2b, Week 1-12), Table 4.5-3 (N-I Arms -1, 1, 2, and 2b, Week 13 and 
following), Table 4.5-4 (N-I Arm 2c), and Table 4.5-5 (N-I Arm 2d combined with cobimetinib).
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Table 4.5-1:
Dosing Schedule for Arm N - Nivolumab (BMS-936558) Monotherapy
Every 2 Week Dosing
Day 1, Week 1
Day 1, Week 3
Day 1, Week 5, 7, 9, 
and every other week thereafter
3 mg/kg Nivolumab 
3 mg/kg Nivolumab 
3 mg/kg Nivolumab 
Table 4.5-2:
Dosing Schedule for N-I Arms -1, 1, 2, and 2b (Week 1-12) - Nivolumab (BMS-936558) + Ipilimumab 
Combination
Every 3 Week Dosing
Study Part
Day 1
Week 1
Day 1
Week 4
Day 1
Week 7
Day 1
Week 10
Dose Escalation Phase 
Dose Level -1
0.3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
0.3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
0.3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
0.3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
Dose Escalation Phase 
Dose Level 1
1 mg/kg Nivolumab 
1 mg/kg Ipilimumab
1 mg/kg Nivolumab 
1 mg/kg Ipilimumab
1 mg/kg Nivolumab 
1 mg/kg Ipilimumab
1 mg/kg Nivolumab 
1 mg/kg Ipilimumab
Dose Escalation Phase 
Dose Level 2
1 mg/kg Nivolumab 
3 mg/kg Ipilimumab
1 mg/kg Nivolumab 
3 mg/kg Ipilimumab
1 mg/kg Nivolumab 
3 mg/kg Ipilimumab
1 mg/kg Nivolumab 
3 mg/kg Ipilimumab
Efficacy, Staged Phasea
Dose Level 2
1 mg/kg Nivolumab 
3 mg/kg Ipilimumab
1 mg/kg Nivolumab 
3 mg/kg Ipilimumab
1 mg/kg Nivolumab 
3 mg/kg Ipilimumab
1 mg/kg Nivolumab 
3 mg/kg Ipilimumab
Dose Level 2b
3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
a The staged phase uses maximum tolerable dose identified in escalation phase since it might be different for each tumor type
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Table 4.5-3:
Dosing Schedule for N-I Arms -1, 1, 2, and 2b (Week 13 and following) - Nivolumab (BMS-936558) + 
Ipilimumab Combination
Every 2 Week Dosing
Day 1
Week 13
Day 1
Week 15
Day 1, Week 17, 19, 21 
and every other week thereafter
3 mg/kg Nivolumab 
3 mg/kg Nivolumab 
3 mg/kg Nivolumab 
Table 4.5-4:
Dosing Schedule for N-I Arm Dose Level 2c - Nivolumab (BMS-936558) + Ipilimumab Combination
Every 2 or 6 Week Dosing
Day 1
Week 1
Day 1, Week 3, 5, 7, 9 
and every other week thereafter
Day 1 Week 7, 13, 19 and every 6 weeks 
thereafter
3 mg/kg Nivolumab 
3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
1 mg/kg Ipilimumab
Table 4.5-5:
Dosing Schedule for N-1 Arm Dose Level 2d Combined with Cobimetinib - Nivolumab (BMS-936558) + 
Ipilimumab + Cobimetinib Combination
Every 2 or 6 Week Dosing
Day 1
Week 1
Day 1, Week 3, 5, 7, 9
and every other week thereafter
Day 1, Week 7, 13, 19
and every 6 weeks thereafter
3 mg/kg Nivolumab 
3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
1 mg/kg Ipilimumab
60 mg cobimetinib
Once daily, 21 days on/7 days off
Once daily, 21 days on/7 days off
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Nivolumab and Ipilimumab combination:
When study drugs (nivolumab or ipilimumab) 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 second infusion will always be ipilimumab, and will start no sooner than 30 minutes after 
completion of the nivolumab infusion.
When cobimetinib is taken on the same day with nivolumab alone or nivolumab in combination 
with ipilimumab, dose timimg for cobimetinib should remain the same as on any other days from 
the 21 consecutive days treatment schedule and should follow the 21 day on/7 days off schedule.
Dosing calculation based on weight:
The dosing calculations should be based on the body weight. If the subject’s weight on the day of 
dosing differs by > 10% from the weight used to calculate the dose, the dose must be 
recalculated. All doses should be rounded to the nearest milligram.
Dosing modifications:
There will be no dose modifications of nivolumab and ipilimumab allowed for the management 
of toxicities of individual subjects.
Dosing window Arm N-I Dose Levels 2 and 2b (Week 1-12): subjects may be dosed no less than 
19 days between doses and no more than 3 days from scheduled dose. If dosing is delayed, both 
nivolumab and ipilimumab must be delayed together. If dosing is resumed after a delay, both 
nivolumab and ipilimumab must be resumed on the same day.
Dosing window Arm N and Arm N-I Dose Levels 2 and 2b (Week 13 and following): subjects 
may be dosed no less than 12 days between doses and no more than 3 days from scheduled dose.
Dosing window Arm N-I Dose Levels 2c: subjects may be dosed no less than 12 days between 
doses and no more than 3 days from scheduled dose. If dosing is delayed, both nivolumab and 
ipilimumab must be delayed together.
Dosing window Arm N-I Dose Level 2d: Cotellic (cobimetinib) will be administered at 60 mg 
(three 20 mg tablets) orally taken once daily with or without food 21 days on/7 days off until 
disease progression or unacceptable toxicity. If a dose of Cotellic is missed or if vomiting occurs 
when the dose is taken, dosing with the next scheduled dose should be resumed. Recommended 
dose reductions are summarized in Sections 3.1.10 and 4.5.3 and provided in the Prescribing 
Information for Cotellic.57
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF.
4.5.1
Antiemetic Premedications
Antiemetic medications should not be routinely administered prior to dosing of drugs. 
See Section 4.5.6 for subsequent premedication recommendations following a nivolumab- or 
ipilimumab-related infusion reaction.
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4.5.2
Dose Delay Criteria
Nivolumab and Ipilimumab
These dose delay criteria apply for all drug-related adverse events attributed to nivolumab, 
ipilimumab, or both. All study drugs must be delayed until treatment can resume (see Section
4.5.4).
Nivolumab and ipilimumab administration should be delayed for the following:

Any Grade 2 non-skin, drug-related adverse event, with the following exceptions:

Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment delay

Any Grade 3 skin drug-related adverse event

Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
asymptomatic amylase or lipase, lymphocytopenia, AST, ALT, or total bilirubin:
Grade 3 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations, or radiographic signs of pancreatitis do not require a dose 
delay. It is recommended to consult with the BMS Medical Monitor for Grade 3 
amylase or lipase abnormalities.
If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, 
delay dosing for drug-related Grade 2 toxicity
If a subject has baseline grade 1 AST, ALT, or total bilirubin elevation, delay dosing 
for drug-related Grade 3 toxicity
Grade 3 lymphocytopenia not associated with symptoms or clinical manifestations. 
It is recommended to consult with the BMS Medical Monitor for Grade 3 
lymphocytopenia before treatment continuation.

Any adverse event, laboratory abnormality, or concurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
Because of the potential for nivolumab- or ipilimumab-related AEs requiring early recognition 
and prompt intervention, management algorithms have been developed for suspected pulmonary 
toxicity, GI toxicity, hepatotoxicity, endocrinopathy, skin toxicity, neurological toxicity, and 
nephrotoxicity.
In order to standardize the management of adverse events for all subjects, treatment management 
algorithms recommended for utilization in Study CA209032 are included in Appendix 2. 
Adverse event treatment management algorithms included in the Nivolumab IB or 
Ipilimumab IB might be considered for individual cases.
Cobimetinib
Dose delay criteria for the management of toxicities of individual subjects taking cobimetinib are 
summarized in Section 4.5.3 and in the prescribing information.57
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4.5.3
Dose Modifications
Intrapatient dose reductions for nivolumab and ipilimumab for the management of toxicities of
individual subjects or dose escalations are not permitted.
Intrapatient dose modifications for cobimetinib for the management of toxicities of individual 
subjects are summarized in Table 4.5.3-1 and in the prescribing information.
Table 4.5.3-1:
Recommended Dose Modifications for COTELLIC for Adverse 
Reactions
Severity of Adverse Reactiona
Dose Modification for COTELLIC
Hemorrhage
Grade 3
Withhold COTELLIC for up to 4 weeks

If improved to Grade 0 or 1, resume next lower dose level

If not improved within 4 weeks, permanently discontinue
Grade 4
Permanently discontinue
Cardiomyopathy
Asymptomatic, absolute decrease in 
LVEF from baseline of greater than 10% 
and less than institutional lower limit of 
normal (LLN)
Withhold COTELLIC for 2 weeks; repeat LVEF.
Resume at next lower dose if all of the following are present

LVEF is at or above LLN AND

Absolute decrease from baseline LVEF is 10% or less.
Permanently discontinue if any of the following are present

LVEF is less than LLN OR

Absolute decrease from baseline LVEF is more than 10%.
Symptomatic LVEF decrease from 
baseline
Withhold COTELLIC for up to 4 weeks, repeat LVEF.
Resume at next lower dose if all of the following are present:

Symptoms resolve and

LVEF is at or above LLN AND

Absolute decrease from baseline LVEF is 10% or less.
Permanently discontinue if any of the following are present

Symptoms persist, OR

LVEF is less than LLN, OR

Absolute decrease from baseline LVEF is more than 10%.
Dermatologic Reactions
Grade 2 (intolerable), Grade 3 or 4
Withhold or reduce dose.
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Table 4.5.3-1:
Recommended Dose Modifications for COTELLIC for Adverse 
Reactions
Severity of Adverse Reactiona
Dose Modification for COTELLIC
Severe Retinopathy or Retinal Vein Occlusion
Serious retinopathy
Withhold COTELLIC for up to 4 weeks.

If signs and symptoms improve, resume at the next lower dose 
level.

If not improved or symptoms recur at the lower dose within 4 
weeks, permanently discontinue.
Retinal vein occlusion
Permanently discontinue COTELLIC.
Liver Laboratory Abnormalities and Hepatotoxicity
First occurrence Grade 4
Withhold COTELLIC for up to 4 weeks.

If improved to Grade 0 or 1, then resume at the next lower 
dose level.
If not improved to Grade 0 or 1 within 4 weeks, permanently 
discontinue
Recurrent Grade 4
Permanently discontinue COTELLIC.
Rhabdomyolysis and Creatine Phosphokinase (CPK) elevations

Grade 4 CPK elevation

Any CPK elevation and myalgia
Withhold COTELLIC for up to 4 weeks.

If improved to Grade 3 or lower, resume at the next lower dose 
level.

If not improved within 4 weeks, permanently discontinue.
Photosensitivity
Grade 2 (intolerable), Grade 3 or Grade 4
Withhold COTELLIC for up to 4 weeks.

If improved to Grade 0 or 1, resume at the next lower dose level.

If not improved within 4 weeks, permanently discontinue.
Other

Grade 
2 
(intolerable) 
adverse 
reactions

Any Grade 3 adverse reactions
Withhold COTELLIC for up to 4 weeks.

If improved to Grade 0 or 1, resume at the next lower dose level.

If not improved within 4 weeks, permanently discontinue.
First occurrence of any Grade 4 adverse 
reaction

Withhold COTELLIC until adverse reaction improves to Grade 
0 or 1. Then resume at the next lower dose level, OR

Permanently discontinue
Recurrent Grade 4 adverse reaction
Permanently discontinue COTELLIC.
a NCI CTCAE v 4.0
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4.5.4
Criteria to Resume Treatment
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to 
Grade 1 or baseline value, with the following exceptions:

Subjects may resume treatment in the presence of Grade 2 fatigue.

Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for 
reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in the 
presence
of Grade 2 AST/ALT OR total bilirubin. Subjects with combined 
Grade 2 AST/ALT AND
total bilirubin values meeting discontinuation parameters 
(Section 4.5.5) should have treatment permanently discontinued.

Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed.

Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement or glucose controlling agents may resume treatment.
If the criteria to resume treatment are met, the subject should restart treatment at the next 
scheduled timepoint per protocol. However, if the treatment is delayed past the scheduled 
timepoint per protocol, the scheduled study treatment administration will be delayed, but not 
skipped, until dosing resumes. In particular, this is to ensure that subjects in Arm N-I will 
receive 4 administrations of combined nivolumab and ipilimumab treatment if toxicity allows.
If dose delay is necessary for subjects in Arm N-I during Week 1-12, both nivolumab and 
ipilimumab must be delayed until treatment can resume. However, if a nivolumab-related 
infusion reaction prevents subsequent infusion of ipilimumab on the same day, the dose of 
ipilimumab should be replaced as soon as possible. In such instances, at least 19 days must 
elapse between the replacement dose of ipilimumab and the administration of the next dose of 
nivolumab combined with ipilimumab.
If treatment is delayed > 6 weeks from the last dose, the subject must be permanently 
discontinued from study therapy, except as specified in Section 4.5.5.
Cobimetinib will be resumed in accordance with the Prescribing Information for Cotellic and 
dose modification summary provided in Section 4.5.3.
4.5.5
Discontinuation Criteria
Nivolumab and Ipilimumab
Discontinuation criteria apply for all drug-related adverse events attributed to nivolumab, 
ipilimumab, or both.
Treatment should be permanently discontinued for the following:

Any Grade 2 drug-related uveitis, eye pain, or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment.
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
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for drug-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, 
diarrhea, colitis, neurologic toxicity, hypersensitivity reactions, and infusion reactions:

Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic 
toxicity, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation

For Grade 3 endocrinopathy adverse events such as adrenal insufficiency, 
ACTH deficiency, hyper- or hypothyroidosis, or glucose intolerance, which resolve or are 
adequately controlled with physiologic hormone replacement (steroids, thyroid 
hormones) or glucose controlling agents, respectively, do not require treatment 
discontinuation

Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except: 
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
Any drug-related liver function test (LFT) abnormality that meets the following 
criteria require discontinuation: 

AST or ALT > 8 x ULN

Total bilirubin > 5 x ULN

Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN

Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events which do not require discontinuation:

Grade 4 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations, or radiographic signs of pancreatitis. Consult with the BMS Medical 
Monitor for Grade 4 amylase or lipase abnormalities.

Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset.

For Grade 4 endocrinopathy adverse events such as adrenal insufficiency, 
ACTH deficiency, hyper- or hypothyroidosis, or glucose intolerance, which resolve or are 
adequately controlled with physiologic hormone replacement (steroids, thyroid 
hormones) or glucose controlling agents, respectively, retreatment can be considered after 
discussion with the BMS Medical Monitor.

Grade 4 lymphocytopenia not associated with symptoms or clinical manifestations. It is 
recommended to consult with the BMS Medical Monitor for Grade 4 lymphocytopenia 
before treatment continuation.
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
Any dosing interruption lasting > 6 weeks with the following exceptions:

Dosing interruptions to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed. Prior to re-initiating treatment in a subject with a dosing interruption 
lasting > 6 weeks, the BMS medical monitor must be consulted. Tumor assessments 
should continue as per protocol even if dosing is interrupted. 

Dosing interruptions > 6 weeks that occur for non-drug-related reasons may be allowed if 
approved by the BMS medical monitor. Prior to re-initiating treatment in a subject with a 
dosing interruption lasting > 6 weeks, the BMS medical monitor must be consulted. 
Tumor assessments should continue as per protocol even if dosing is interrupted.

Any adverse event, laboratory abnormality, or concurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued nivolumab,
ipilimumab, or cobimetinib dosing.
If a subject in Arm N-I meets criteria for discontinuation of nivolumab, the subject should 
discontinue both nivolumab and ipilimumab and be taken off the treatment phase of the study 
entirely. However, if the investigator assesses the drug-related AE to be related to ipilimumab 
only and not related to nivolumab, ipilimumab dosing alone may be discontinued while 
nivolumab dosing is delayed until the subject meets criteria to resume nivolumab treatment 
(specified in Section 4.5.4). Nivolumab would be continued at 3 mg/kg with an every 2 week 
dosing interval. The relationship to ipilimumab should be well documented in the source 
documents and the BMS medical monitor needs to be contacted prior to continuation with 
nivolumab therapy.
Cobimetinib
Discontinuation criteria for cobimetinib are specified in Section 4.5.3 and in the Prescribing 
Information.57
For subjects on Arm N-I dose level 2d, if the investigator assesses drug related AEs to be related 
to ipilimumab or cobimetinib only and not related to other study drugs, treatment with the agent 
causing the AE alone may be permanently discontinued and treatment with the remaining drugs 
will continue. Treatment with the remaining drugs may only be resumed when the subject meets 
criteria to resume treatment according to section 4.5.4. If a subject in Arm N-I dose level 2d 
meets criteria for discontinuation of nivolumab or nivolumab and ipilimumab, the subject should 
discontinue all agents, nivolumab, ipilimumab, and cobimetinib and be taken off the treatment 
phase of the study entirely. 
4.5.6
Treatment of Nivolumab- or Ipilimumab-Related Infusion Reactions
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, each 
is unlikely to be immunogenic and induce an infusion or hypersensitivity reaction. However, if 
such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritis, 
arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion 
reactions should be reported within 24 hours to the BMS Medical Monitor and reported as an 
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SAE if criteria are met. Infusion reactions should be graded according to NCI CTCAE 
(version 4.0) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate: 
For Grade 1 symptoms (Mild reaction; infusion interruption not indicated; intervention not 
indicated):
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes before 
additional nivolumab or ipilimumab administrations.
For Grade 2 symptoms (Moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for 
24 hours):
Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the infusion 
is interrupted, restart the infusion at 50% of the original infusion rate when symptoms resolve; if 
no further complications ensue after 30 minutes, the rate may be increased to 100% of the 
original infusion rate. Monitor subject closely. If symptoms recur then no further nivolumab or 
ipilimumab will be administered at that visit. Administer diphenhydramine 50 mg IV, and 
remain at bedside and monitor the subject until resolution of symptoms. The amount of study 
drug infused must be recorded on the electronic case report form (eCRF). The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) should be administered at 
least 30 minutes before additional nivolumab or ipilimumab administrations. If necessary, 
corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may be 
used.
For Grade 3 or Grade 4 symptoms (Severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[eg, renal impairment, pulmonary infiltrates]; Grade 4: (life threatening; pressor or ventilatory 
support indicated):
Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV infusion of normal 
saline, and treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of 
a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected 
slowly 
for 
IV 
administration, 
and/or 
diphenhydramine 
50 mg 
IV 
with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored until the 
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investigator is comfortable that the symptoms will not recur. Nivolumab or ipilimumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor subject until recovery from symptoms. 
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritis within 1 week after treatment), symptomatic treatment may be given 
(eg, oral antihistamine, or corticosteroids).
4.5.7
Treatment Beyond Disease Progression
As described in Section 1.1.11 accumulating evidence indicates that subjects treated with 
immunotherapy may derive clinical benefit despite evidence of PD.84
Subjects will be permitted to continue with treatment beyond initial RECIST 1.1 defined PD as 
long as they meet the following criteria:

Investigator-assessed clinical benefit
and

Subject is tolerating study drug.
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. The following 
criteria need to be taken into consideration:

Absence of clinical symptoms and signs (including worsening of laboratory values) 
indicating disease progression.

No decline in ECOG performance status.

Absence of rapid progression of disease or of progressive tumor at critical anatomical sites 
(eg, cord compression) requiring urgent alternative medical intervention.
Treatment with cobimetinib beyond progression as monotherapy or as part of the combination 
with nivolumab and ipilimumab is not permitted.
All decisions to continue treatment beyond progression must be discussed with the BMS Medical 
Monitor and documented in the study records.
Subjects must be re-consented in order to continue treatment.
Subjects should discontinue study therapy upon evidence of further progression, defined as an 
additional 10% or greater increase in tumor burden from time of initial progression (including all 
target lesions and new measurable lesions). Progression in non-target lesions should only be 
unequivocal as defined and described in Appendix 3 compared to initial progression.
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 
15 mm). 
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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. Subjects who have tumor shrinkage following RECIST-defined progression (ie, immune 
related response; Section 5.4.4 will be also descriptively summarized separately since these 
immune responses may be used in determining Go to Stage 2.
4.5.8
Crossover to Arm N-I
Subjects in Arm N may crossover to Arm N-I if all of the criteria defined in Section 3.1.6 are
met. Subjects from the SCLC expansion cohort enrolled under or after Amendment 09 are 
excluded from the crossover option. In case Dose Level 2b has been activated and completed the 
safety assessment, subjects for cross over will be assigned to Dose Level 2 or Dose Level 2b
after discussion between the sponsor and investigator taking into consideration previous safety 
and efficacy signals at these dose levels and the status of the individual subject planned for cross 
over.
Before crossover, the investigator should discuss the individual case with the medical monitor 
and document in the study records. 
Subjects must be re-consented prior to crossing over to Arm N-I.
Subjects crossing over to Arm N-I will start treatment at Day 1 Week 1 as described for subjects 
originally randomized to Arm N-I. Subjects who crossed over and subsequently have an 
objective response in Arm N-I, will not be considered in respect to the decision making for 
Arm N-I of proceeding to Stage 2. Subjects in Arm N-I cannot crossover to Arm N.
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 15 mm). 
For statistical analyses that include the investigator-assessed progression date, subjects who 
crossover after 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 in 
Arm N. The tumor assessment confirming PD in Arm N will serve as the baseline for tumor 
assessments in Arm N-I.
4.6
Blinding/Unblinding
Not applicable.
4.7
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF.
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site. 
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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 disposal 
vendor must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible 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 provided that appropriate records of disposal are 
kept.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible 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 provided that appropriate records of disposal are 
kept.
4.10
Retained Samples for Bioavailability / Bioequivalence
Not applicable.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (CA209032)
Procedure
Screening
Visit
Notes
Eligibility Assessments
Informed Consent
X
May be performed more than 28 days prior to the first dose (must be completed prior to any 
study related procedures) 
Original IC in screening for protocol participation; 
Study allows for re-enrollment of a subject that has discontinued the study as a pre-treatment 
failure. If re-enrolled, the subject must be re-consented and assigned a new subject number 
from IVRS.
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed prior to first 
dose.
Demographics and Medical History
X
For SCLC and Ovarian cancer subjects, evaluation of Platinum-free interval (PFI) from the 
completion of any platinum-based chemotherapy and subsequent disease progression, and 
Treatment-free-interval (TFI) from the completion of any other cytotoxic or targeted based 
prior treatment line and subsequent disease progression will be collected. For Ovarian Cancer, 
information about BRCA and Homologous Recombinant Deficiency (HRD), if available, will 
be collected
Tumor Tissue Samples
X
Sufficient tumor tissue obtained before start of study treatment in the metastatic setting or 
from an unresectable site (block or minimum of 10 slides for bladder and SCLC subjects and a 
minimum of 15 slides for ovarian subjects (if medically justified), obtained from core biopsy, 
punch biopsy, excisional biopsy or surgical specimen). Tumor tissue samples must be shipped 
from site to central laboratory prior to randomization.
Screening/Baseline Tumor Assessment
X
CT chest, CT or MRI brain, abdomen, pelvis and all known sites of disease within 28 days 
prior to first dose. For patients with known brain metastasis, an MRI brain is required at 
baseline. A CT brain is not allowed for patients with a history or evidence of known brain 
metastasis at baseline.
Safety Assessments
Physical Examination
X
Within 14 days prior to first dose
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Table 5.1-1:
Screening Procedural Outline (CA209032)
Procedure
Screening
Visit
Notes
Vital Signs and oxygen saturation
X
Including BP, HR, temperature, and oxygen saturation by pulse oximetry (at rest). Obtain vital 
signs at the screening visit and within 72 hours prior to first dose. 
Physical Measurements (including 
performance status)
X
Height, Weight and ECOG status. Within 14 days prior to first dose
Echocardiogram (additional pancreatic 
cancer cohort only)
X
Subjects with LVEF below the institutional LLN or < 50%, whichever is lower, and corrected 
QT 450 ms are to be excluded
ECG
X
Within 14 days prior to first dose
Assessment of Signs and Symptoms
X
Within 14 days prior to first dose
Laboratory Tests
X
CBC w/differential, Chemistry panel including: LDH, AST, ALT, ALP, T.Bili, BUN or serum 
urea level, creatinine, albumin, Ca, Mg, Na, K, Cl, glucose, amylase, lipase, TSH, Free T4, 
Free T3, hepatitis B surface antigen (HBV sAg), and hepatitis C antibody (HCV Ab) or 
Hepatitis C RNA (HCV RNA), CPK (additional pancreatic cancer cohort only) within 14 days
prior to first dose. Screening labs done within 72 hours prior to first dose can also be used for 
on treatment lab purposes at Day 1 dosing.
Pregnancy Test (WOCBP only)
X
Serum or urine within 24 hours of first dose
Ophthalmological evaluation 
(additional pancreatic cancer cohort 
only)
X
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Table 5.1-2:
On-Study Assessments - Arm N, Nivolumab Monotherapy (CA209032)
Procedure
For Arm N, Nivolumab is 
administered every 2 weeks
Notes
Day 1
Week 1, 3, 5, 7, 9, etc
Safety Assessments
Targeted Physical Examination
X
Within 72 hours prior to dosing. During treatment hold to be conducted every 12 
weeks to adjust to the tumor assessment schedule (see Section 3.1.6).
Vital Signs and Oxygen Saturation
X
Including BP, HR, temperature, and oxygen saturation by pulse oximetry. Pulse 
oximetry at rest and within 72 hours prior to dosing. During treatment hold to be 
conducted every 12 weeks to adjust to the tumor assessment schedule (see Section 
3.1.6).
Physical Measurements (including 
performance status)
X
Weight and ECOG status. 
The dosing calculations should be based on the body weight. If the subject’s weight 
on the day of dosing differs by > 10% from the weight used to calculate the dose, the 
dose must be recalculated. All doses should be rounded to the nearest milligram.
During treatment hold to be conducted every 12 weeks to adjust to the tumor 
assessment schedule (see Section 3.1.5).
Adverse Events Assessment
Continuously
eSAEs should be approved in TAO within 5 days from entry
Laboratory Tests
X
On-study local laboratory assessments should be done within 72 hours prior to each 
dose up to and including Week 25 and then every other dose thereafter (Week 29, 
Week 33, Week 37 etc.) and include: CBC w/differential, LFTs (ALT, AST, total 
bilirubin, alkaline phosphatase), BUN or serum urea level, creatinine, albumin, Ca, 
Mg, Na, K, Cl, LDH, glucose, amylase, lipase, TSH (if TSH result abnormal, 
subsequent testing of Free T4 and Free T3 required).
During treatment hold to be conducted every 12 weeks to adjust to the tumor 
assessment schedule (see Section 3.1.5).
Pregnancy Test (WOCBP only)
X
Serum or urine within 24 hours prior to first dose and then every 4 weeks. During
treatment hold to be conducted every 12 weeks and resume per protocol testing once 
treatment resumes (see Section 3.1.5).
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Table 5.1-4:
On-Study Assessments - N-I Arms (Dose Levels 2 and 2b), Week 13 and following, Nivolumab + 
Ipilimumab Combination (CA209032)
Procedure
Week 13 and following, Nivolumab 
is administered every 2 weeks
Notes
Day 1
Week 13, 15, 17, 19, 21, etc
Peripheral Blood RNA
See Section 5.6.8.6 for details 
regarding specific sample timing
Peripheral Blood Mononuclear 
Cells (PBMCs)
See Section 5.6.8.6 for details 
regarding specific sample timing
Any time PBMC is performed please also draw CBC for white blood cell 
counts, if not already part of the visit lab draws.
Whole Blood Sample (DNA)
See Section 5.6.8.6 for details 
regarding specific sample timing
Pharmacokinetic Assessments
PK Samples
See Section 5.5.1 for details regarding 
specific sample timing
Efficacy Assessment
Tumor Assessment
See Notes
Tumor assessments should occur every 6 weeks (1 wk) from first dose 
for the first 24 weeks, then every 12 wks (1 wk) while on treatment or 
on treatment hold due to any reason until disease progression and 
treatment discontinuation, whichever occurs later. Additionally, with the 
exception of crossover participants, tumor assessments will not be 
required upon initiation of subsequent anti-cancer therapy.
CT chest, CT or MRI abdomen, pelvis and all known sites of disease. Use 
same imaging method as was used at screening/baseline.
Subjects with a history of brain metastasis should have surveillance MRI 
approximately every 12 weeks, or sooner if clinically indicated
Clinical Drug Supplies
IVRS Drug Vial Assignment
X
Administer Study Treatment
X
Subjects may be dosed no less than 12 days between doses and no more than 
3 days from the scheduled dose.
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Table 5.1-5:
On-Study Assessments for N-I Arms (Dose Level 2c) Nivolumab + Ipilimumab Combination 
(CA209032)
Procedure
For Arm N-I Dose level 2c, Nivolumab is 
administered every 2 weeks, Ipilimumab is 
administered every 6 weeks
Notes
Day 1
Week 1, 3, 5, 7, 9, etc
Laboratory Tests
X
Within 72 hours prior to each dose up to and including Week 25 and 
then every other dose thereafter (Week 29, Week 33, Week 37 etc.). 
Dosing to include CBC w/ differential, LFTs, BUN or serum urea 
level, creatinine, albumin, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, 
lipase, TSH (if TSH result abnormal, subsequent testing of Free T4 and 
Free T3 required).
During treatment hold to be conducted every 12 weeks to adjust to the 
tumor assessment schedule (see Section 3.1.5).
Pregnancy Test (WOCBP only)
X
Serum or urine within 24 hours prior to first dose and then every 4
weeks. During treatment hold to be conducted every 12 weeks and 
resume per protocol testing once treatment resumes (see Section 3.1.5).
Outcomes Research Assessments
QoL
X
Collect EQ-5D prior to study drug administration through Week 13, 
then at the same time of subsequent tumor assessments, during Follow 
Up 1 and 2 and survival visits. The EQ-5D can be done via a phone 
contact when a clinic visit is not feasible (ie., follow up scans are being 
done at another facility or department) in order to not miss the 
assessment.
During treatment hold to be conducted every 12 weeks to adjust to the 
tumor assessment schedule (see Section 3.1.5).
Pharmacokinetic Assessments
PK Samples
See Section 5.5.1 for details regarding 
specific sample timing
 
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BMS-936558 / BMS-734016
nivolumab / ipilimumab
Table 5.1-5:
On-Study Assessments for N-I Arms (Dose Level 2c) Nivolumab + Ipilimumab Combination 
(CA209032)
Procedure
For Arm N-I Dose level 2c, Nivolumab is 
administered every 2 weeks, Ipilimumab is 
administered every 6 weeks
Notes
Day 1
Week 1, 3, 5, 7, 9, etc
Clinical Drug Supplies
IVRS Drug Vial Assignment
X
Administer Study Treatment
X
See Section 4.5, Note: Within 3 days from vial allocation, the subject 
must receive the first dose of study medication. Subjects may be dosed 
no less than 12 days between doses and no more than 3 days from the 
scheduled dose.
Table 5.1-6:
On-Study Assessments for N-I Arms (Dose Level 2d) Nivolumab + Ipilimumab + Cobimetinib
Combination (CA209032)
Procedure
For Arm N-I Dose level 2d, Nivolumab is 
administered every 2 weeks, Ipilimumab is 
administered every 6 weeks, cobimetinib is 
administered orally 21 days on/7 days off
Notes
Day 1
Week 1, 3, 5, 7, 9, etc
Safety Assessments
Targeted Physical Examination
X 
Within 72 hours prior to dosing. During treatment hold to be 
conducted every 12 weeks to adjust to the tumor assessment 
schedule (see Section 3.1.6).
Vital Signs and Oxygen Saturation
X
Including BP, HR, temperature, and oxygen saturation by pulse 
oximetry. Pulse oximetry at rest within 72 hours prior to dosing. 
During treatment hold to be conducted every 12 weeks to adjust to 
the tumor assessment schedule (see Section 3.1.6).
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Table 5.1-6:
On-Study Assessments for N-I Arms (Dose Level 2d) Nivolumab + Ipilimumab + Cobimetinib
Combination (CA209032)
Procedure
For Arm N-I Dose level 2d, Nivolumab is 
administered every 2 weeks, Ipilimumab is 
administered every 6 weeks, cobimetinib is 
administered orally 21 days on/7 days off
Notes
Day 1
Week 1, 3, 5, 7, 9, etc
sample timing
Peripheral Blood Mononuclear 
Cells (PBMCs)
See Section 5.6 for details regarding specific 
sample timing
Any time PBMC is performed please also draw CBC for white 
blood cell counts, if not already part of the visit lab draws.
Whole Blood Sample (DNA)
See Section 5.6 for details regarding specific 
sample timing
Pharmacogenetic research
Optional (refer to Amendment 01 and 07)
Efficacy Assessment
Tumor Assessment
See Notes
For participants who discontinue treatment for reasons other than 
disease progression.
Tumor assessments should occur every 6 weeks (1 wk) from first 
dose for the first 24 weeks, then every 12 wks (1 wk) while on 
treatment or on treatment hold due to any reason until disease 
progression and treatment discontinuation, whichever occurs later. 
Additionally, with the exception of crossover participants, tumor 
assessments will not be required upon initiation of subsequent anti-
cancer therapy. 
CT chest, CT or MRI abdomen, pelvis and all known sites of 
disease. Use same imaging method as was used at 
screening/baseline.
Subjects with a history of brain metastasis should have 
surveillance MRI approximately every 12 weeks, or sooner if 
clinically indicated
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Table 5.1-6:
On-Study Assessments for N-I Arms (Dose Level 2d) Nivolumab + Ipilimumab + Cobimetinib
Combination (CA209032)
Procedure
For Arm N-I Dose level 2d, Nivolumab is 
administered every 2 weeks, Ipilimumab is 
administered every 6 weeks, cobimetinib is 
administered orally 21 days on/7 days off
Notes
Day 1
Week 1, 3, 5, 7, 9, etc
Clinical Drug Supplies
IVRS Drug Vial Assignment
X
Administer Study Treatment
X
Nivolumab is administered every 2 weeks, 
Ipilimumab is administered every 6 weeks, 
cobimetinib is administered orally at 60 mg 
(three 20 mg tablets) qd 21 days on/7 days off
See Section 4.5, Note: Within 3 days from vial allocation, the 
subject must receive the first dose of study medication. Subjects 
may be dosed with nivolumab alone or nivolumab and ipilimumab 
no less than 12 days between doses and no more than 3 days from 
the scheduled dose.
Nivolumab and Ipilimumab both administered as 30-min IV 
infusion.
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Table 5.1-7:
Follow-up Assessments (CA209032) - All Subjects
Procedure
Follow Up,a
Visits 1 and 2
Survival,b
Follow up Visits
Notes
Outcomes Research Assessments
QoL
X
X
Collect EQ-5D prior to study drug administration through Week 13, then at 
the same time of subsequent tumor assessments, during Follow Up 1 and 2 
and survival visits. The EQ-5D can be done via a phone contact when a 
clinic visit is not feasible (ie, follow up scans are being done at another 
facility or department) in order to not miss the assessment.
Pharmacokinetic Samples
PK Samples
X
See Section 5.5.1 for schedule of assessments
a Follow-up visit 1 (FU1) = 35 days from the last dose 7 days or coincide with the date of discontinuation (7 days) if date of discontinuation is greater than 
42 days after last dose, Follow-up visit 2 (FU2) = 80 days (7 days) from follow-up visit 1
b Survival visits = every 3 months from FU2 (±14 days) from FU2.
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
5.1.1
Retesting During Screening or Lead-in Period
Laboratory parameters and/or assessments that are included in Table 5.1-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified subjects. Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
5.2
Study Materials

NCI CTCAE version 4.0

BMS-936558 (nivolumab) Investigator Brochure

Ipilimumab Investigator Brochure

Laboratory manuals for collection and handling of blood (including biomarker and 
immunogenicity) and tissue specimens

Site manual for operation of interactive voice response system, including enrollment 
worksheets

Site manual for imaging process and requirements

Manual for entry of local laboratory data

Serious Adverse Events (or eSAE) case report form pages

Pregnancy surveillance forms

RECIST 1.1 pocket guide
5.3
Safety Assessments
At baseline, a medical history will be obtained to capture relevant underlying conditions. The 
baseline examinations should include signs and symptoms, weight, height, ECOG Performance 
Status, BP, HR, temperature, and oxygen saturation by pulse oximetry at rest should be 
performed within 14 days prior to first dose except where noted in
 
 
 
Baseline local laboratory assessments should be done within 14 days prior to the first dose and 
include: CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or 
serum urea level, creatinine, albumin, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, lipase, TSH, 
Free T4, Free T3, and Hep B and C testing (HBV sAg and HCV RNA or Ab) and CPK 
(additional pancreatic cancer cohort only) (see Table 5.1-1). Pregnancy testing for WOCBP 
(done locally) must be performed within 24 hours prior to the initial administration of study drug 
at baseline and then every 3 weeks for subjects in Arm N-I at Week 1-12, then every 4 weeks, 
and at the safety follow up visits. For subjects in Arm N and N-I 2c pregnancy testing for 
WOCBP (done locally) must be performed within 24 hours prior to the initial administration of 
study drug at baseline and then every 4 weeks, and at each safety follow up visit. During 
treatment hold, pregnancy testing must be performed every 12 weeks and resumed per protocol 
testing once treatment resumes.
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BMS-936558 / BMS-734016
nivolumab / ipilimumab
Subjects will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be performed continuously during the treatment phase. During the safety follow-up phase 
(Table 5.1-4) toxicity assessments should be done in person. Once subjects reach the survival 
follow-up phase, either in-person visits or documented telephone calls to assess the subject’s 
status are acceptable.
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.0.
On-study weight, ECOG performance status, and vital signs should be assessed at each on-study 
visit prior to nivolumab dosing. Vital signs should also be taken as per institutional standard of 
care prior to, during and after dosing. Oxygen saturation by pulse oximetry at rest should be 
assessed at each on study visit prior to nivolumab dosing. The start and stop time of the 
nivolumab and the ipilimumab infusion should be documented. Physical examinations are to be 
performed as clinically indicated. If there are any new or worsening clinically significant 
changes since the last exam, report changes on the appropriate non-serious or serious adverse 
event page.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
inducted 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.
Oxygen saturation by pulse oximetry should be obtained prior to each dose of nivolumab or 
ipilimumab and at any time a subject has any new or worsening respiratory symptoms. A reading 
at rest should be obtained at each time point. If a subject shows changes on pulse oximetry or 
other pulmonary-related signs (eg, hypoxia, fever) or symptoms (eg, dyspnea, cough) consistent 
with possible pulmonary adverse events, the patient subject should be immediately evaluated to 
rule out pulmonary toxicity. An algorithm for the management of suspected pulmonary toxicity 
can be found in Appendix 2.
Echocardiogram and ophthalmologic examination (including retinal evaluation) to be conducted
by an ophthalmologist will be performed for the additional pancreatic cancer cohort only.
Some of the previously referred to assessments may not be captured as data in the eCRF. They
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
5.3.1
Imaging Assessment for the Study
Images will be submitted to an imaging core lab for central review. Sites will be trained prior to 
scanning the first study subject. Image acquisition guidelines and submission process will be 
outlined in the CA209032 Imaging Manual to be provided by the core lab. Any incidental 
findings of potential clinical relevance that are not directly associated with the objectives of the 
protocol should be evaluated and handled by the Study Investigator as per standard 
medical/clinical judgment.
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
CT/MRI 
Contrast-enhanced Computed Tomography (CT) scans acquired on dedicated CT equipment is 
preferred for this study. CT with contrast of the chest, abdomen and pelvis are to be performed 
for tumor assessments at baseline and beginning 6 weeks (+/- 1 week) from first dose and 
continuing every 6 weeks (+/- 1 week) for the first 24 weeks and every 12 weeks (+/- 1 week) 
thereafter, while on treatment or on treatment hold for any reason until disease progression and 
treatment discontinuation, whichever occurs later. Additionally, with the exception of crossover 
participants, tumor assessments will not be required upon initiation of subsequent anti-cancer 
therapy. CT scans should be acquired with 5mm slices with no intervening gap (contiguous).
Although a contrast enhanced CT in particular for the chest is the preferred technique, a contrast 
enhanced MRI may be used based on local standards.
Should a subject have a contraindication for CT IV contrast, a non-contrast CT of the chest and a 
contrast enhanced MRI of the abdomen and pelvis may be obtained. MRI’s should be acquired 
with slice thickness of £5 mm with no gap (contiguous). 
Every attempt should be made to image each subject using an identical acquisition protocol on 
the same scanner for all imaging time points.
Note: Use of CT component of a PET/CT scanner:
Combined modality scanning such as with FDG-PET/CT is increasingly used in clinical care, 
and is a modality/technology that is in rapid evolution; therefore, the recommendations outlined 
here may change rather quickly with time. At present, low dose or attenuation correction CT 
portions of a combined FDG-PET/CT are of limited use in anatomically based efficacy 
assessments and it is therefore suggested that they should not be substituted for dedicated 
diagnostic contrast enhanced CT scans for anatomically based RECIST measurements. However, 
if a site can document that the CT performed as part of a FDG-PET/CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast) then the CT portion of the FDG-PET/CT 
can be used for RECIST 1.1measurements. Note, however, that the FDG-PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.
MRI Brain
MRI or CT of brain is required at screening in order to rule out active metastatic disease. For 
patients with a history of known brain metastasis, an MRI brain is required at baseline. A CT 
brain is not allowed for patients with known brain metastasis at baseline. Subjects with a history 
of brain metastasis should have surveillance MRI approximately every 12 weeks, or sooner if 
clinically indicated.
5.4
Efficacy Assessments
Study evaluations will take place in accordance with the flow charts in Section 5.1. Baseline 
assessments should be performed within 28 days prior to the first dose utilizing CT or MRI. In 
addition to chest, abdomen, pelvis, and brain, all known sites of disease should be assessed at 
baseline. Subsequent assessments should include chest, abdomen, and pelvis, and all known sites 
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CA209032
BMS-936558 / BMS-734016
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of disease and should use the same imaging method as was used at baseline. Subjects will be 
evaluated for tumor response beginning 6 weeks (1 week) from first dose and continuing every 
6 weeks (1 week) for the first 24 weeks and every 12 weeks (1 week) thereafter, while on 
treatment or on treatment hold for any reason until disease progression and treatment 
discontinuation, whichever occurs later. Additionally, with the exception of crossover 
participants, tumor assessments will not be required upon initiation of subsequent anti-cancer 
therapy. Tumor assessments for ongoing study treatment decisions will be completed by the 
investigator using RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria 
(Appendix 3).
5.4.1
Primary Efficacy Assessment
The primary endpoint is objective response rate (ORR) in all assigned subjects as determined by 
the investigators. ORR is defined as the number of subjects with a best overall response (BOR) 
of complete response (CR) or partial response (PR) divided by the number of assigned subjects. 
The investigator-determined ORR will be further characterized by the investigator-determined 
duration of response (DOR) and the magnitude of reduction in tumor volume. ORR and DOR 
will be assessed by BICR in selected tumor types.
5.4.2
Best Overall Response
The best overall response is determined once all the data for the subject is known. It is defined as 
the best response designation, as determined by the investigator or BICR for selected tumor 
types, recorded between the date of first treatment and the date of objectively documented 
progression per RECIST1.1 or the date of subsequent therapy, whichever occurs first. For 
subjects without documented progression or subsequent therapy, all available response
designations will contribute to the BOR assessment. 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.
Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point (minimum 4 weeks after criteria of objective response are first met). In 
this circumstance, the best overall response can be interpreted as in Table 5.4.2-1.
Table 5.4.2-1:
Best overall response when confirmation of CR and PR required
Overall Response 
First Timepoint
Overall Response 
Subsequent Timepoint
Best Overall response
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, 
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Table 5.4.2-1:
Best overall response when confirmation of CR and PR required
Overall Response 
First Timepoint
Overall Response 
Subsequent Timepoint
Best Overall response
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
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable.
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR).
Best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not 
CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best 
response is PR.
For purposes of this study, the minimum scan time from baseline for determination of SD will be 
6 weeks.
5.4.3
Duration of Objective Response
The duration of objective response is measured from the time measurement criteria are first met 
for confirmed CR/PR (whichever is first recorded) until the first date that progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study).
5.4.4
Immune related Response Criteria
Immune related response criteria using unidimensional measurements may be used to describe 
tumor shrinkage following RECIST 1.1 defined disease progression.83 The methodology is the 
same as described above for RECIST 1.1 except for:

New lesions do not automatically denote disease progression

The measurement of longest diameter of new measurable lesions are in included in the sum 
of the measurements of the original target lesions.
Best immune related responses, for subjects who have progression followed by tumor shrinkage 
are classified as irCR (disappearance of all lesions) or irPR (30% reduction from baseline).
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CA209032
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5.5
Pharmacokinetic Assessments
Serum samples for nivolumab and ipilimumab PK and immunogenicity assessments will be 
collected for all subjects.
5.5.1
Pharmacokinetics: Collection and Processing
A detailed schedule of PK and immunogenicity evaluations is provided in Table 5.5.1-1, Table 
5.5.1-2, Table 5.5.1-3, and Table 5.5.1-4. All timepoints are relative to the start of study drug 
administration. Pre-dose samples should be taken within 30 minutes prior to the start of the first 
infusion for the day (prior to the nivolumab dose). All on-treatment PK timepoints are intended 
to align with days on which study drug is administered, if dosing occurs on a different day due to 
minor scheduling shifts, the PK sampling should be adjusted accordingly. If PK and 
immunogenicity samples are drawn but study drug(s) is not administered on the same day, 
samples will be retained and analyzed as planned. There is no need to collect another sample 
when the dose is resumed. Further details of sample collection, processing, and shipment will be 
provided in the laboratory procedures manual.
Table 5.5.1-1:
Pharmacokinetic & Immunogenicity Sampling Schedule - Arm N-I
(Dose level 2 and 2b)
Study Daya
Event
Time 
(Relative 
to Start of 
Infusion)
Hour: Min
Nivolumab 
PK
Blood 
Sample
Nivolumab 
Immunogenicity
Sample
Ipilimumab 
PK
Blood 
Sample
Ipilimumab 
Immunogenicity
Sample
D1 Week 1
Predoseb
00:00
X
X
X
X
D1 Week 4
Predose
00:00
X
X
X
X
D1 Week 10
Predose
00:00
X
X
X
X
D1 Week 13
Predose
00:00
X
X
D1 Week 25
Predose
00:00
X
X
Day 1 of every 
16th week 
until 
discontinuation 
of study 
treatment or 
completion of 
2 years of 
study 
treatment
Predose
00:00
X
X
a If ipilimumab is discontinued and nivolumab continues, ipilimumab PK and Immunogenicity should be collected 
only for the next 2 timepoints (corresponding to ipilimumab sample collection) according to the PK table. If 
ipilimumab is discontinued, nivolumab will follow the same schedule as originally planned for that subject.
b Predose samples for nivolumab and ipilimumab should both be collected prior to start of nivolumab infusion 
(preferably within 30 minutes). If the infusion is delayed and a pre-dose sample is already collected, there is no 
need to collect an additional pre-dose sample.
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Table 5.5.1-2:
Pharmacokinetic & Immunogenicity Sampling Schedule - Arm N
Study Day
Event
Time 
(Relative to 
Start of 
Infusion)
Hour: Min
Nivolumab 
PK
Blood 
Sample
Nivolumab 
Immunogenicity
Sample
Ipilimumab 
PK
Blood 
Sample
Ipilimumab 
Immunogenicity
Sample
All Subjects in Arm N
D1 Week 1
Predose
00:00
X
X
D1 Week 3
Predose
00:00
X
X
D1 Week 5
Predose
00:00
X
X
D1 Week 13
Predose
00:00
X
X
Day 1 of every 
16th week until 
discontinuation 
of study 
treatment or 
completion of 2 
years of study 
treatment
Predose
00:00
X
X
Crossover Subjects Only (SCLC subjects from the expansion cohorts under or after Amendment 09 are 
excluded from this option)
Crossover D1 
Week 1
Predosea
00:00
X
X
X
X
Crossover D1 
Week 4
Predose
00:00
X
X
X
X
Crossover D1 
Week 10
Predose
00:00
X
X
X
X
Crossover D1 
Week 13
Predose
00:00
X
X
Crossover D1 
Week 25
Predose
00:00
X
X
Day 1 of every 
16th week until 
discontinuation 
of study 
treatment or 
completion of 2 
years of study 
treatment
Predose
00:00
X
X
a Predose samples for nivolumab and ipilimumab should both be collected prior to start of nivolumab infusion 
(preferably within 30 minutes). If the infusion is delayed and a pre-dose sample is already collected, there is no 
need to collect an additional pre-dose sample.
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Table 5.5.1-3:
Pharmacokinetic & Immunogenicity Sampling Schedule - Arm N-I 
(Dose level 2c)
Study Daya
Event
Time 
(Relative 
to Start of 
Infusion)
Hour: Min
Nivolumab 
PK
Blood 
Sample
Nivolumab 
Immunogenicity
Sample
Ipilimumab 
PK
Blood 
Sample
Ipilimumab 
Immunogenicity
Sample
D1 Week 1
Predoseb
00:00
X
X
X
X
D1 Week 7
Predose
00:00
X
X
X
X
D1 Week 19
Predose
00:00
X
X
X
X
After Week 19 
Day 1, Day 1 
of every 18th 
week until 
discontinuation 
of study 
treatment or 
completion of 
2 years of 
study 
treatment
Predose
00:00
X
X
X
X
a If ipilimumab is discontinued and nivolumab continues, ipilimumab PK and Immunogenicity should be collected 
only for the next 2 timepoints (corresponding to ipilimumab sample collection) according to the PK table.
b Predose samples for nivolumab and ipilimumab should both be collected prior to start of nivolumab infusion 
(preferably within 30 minutes). If the infusion is delayed and a pre-dose sample is already collected, there is no 
need to collect an additional pre-dose sample.
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Table 5.5.1-4:
Pharmacokinetic & Immunogenicity Sampling Schedule for Arm N-
I Combined with Cobimetinib (Dose level 2d) (Nivolumab and 
Ipilimumab Sample Collections)
Study Day
(1 Cycle =6 
Weeks)
Event
Time 
(Relative to 
Start of 
Infusion)
Hour: Min
Nivolumab 
PK
Blood 
Sample
Nivolumab 
Immunogenicity 
Sample
Ipilimumab 
PK
Blood 
Sample
Ipilimumab 
Immunogenicit
y Sample
D1 Week 1 
(D1 Cycle 1)
predose 
00:00
X
X
X
X
D1 Week 3
(D15 Cycle 1)
predose
00:00
X
X
X
X
D1 Week 9
(D15 Cycle 2)
predose
00:00
X
X
X
X
D1 Week 15
(D15 Cycle 3)
predose
00:00
X
X
X
X
D1 Week 21
(D15 Cycle 4)
predose
00:00
X
X
X
X
Day 1 of every 
24th (4 cycles) 
week after week 
21 until 
discontinuation 
of study 
treatment or 
completion of 2 
years of study 
treatment
predose
00:00
X
X
X
X
Note: Predose samples should be collected just prior to the start of infusion on the day the study drug is administered
5.6
Biomarker Assessments
5.6.1
Rationale and Aims for Biomarker Assessments
The biological basis of nivolumab and ipilimumab in the treatment of oncological disease is to 
modulate the immune system to both generate and restore a durable anti-tumor response leading 
to clearance of tumor. The clinical data generated with the monotherapy and combination 
therapy supports the hypothesis that blockade of PD-1 and CTLA-4 pathways results in rejection 
of tumor by the host immune system.
The precise mechanisms by which nivolumab and ipilimumab exert their anti-tumor activity is 
unclear, however, particular cell types, such as effector T cells and regulatory T cells are critical 
for the anti-tumor response. Nivolumab and ipilimumab appear to have distinct mechanisms of 
action, based on signaling of the PD-1 and CTLA-4 pathways, and the observations of a rise in 
Absolute Lymphocyte Count elevations in ipilimumab, but not nivolumab, therapy. In addition, 
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the role of the MEK inhibitor cobimetinib in recruiting intratumoral CD8 T cells and the 
upregulation of class I MHC may be investigated.
Therefore, the major hypotheses that will be addressed by the biomarker plan for CA209032 are: 

Does Expression of PD-L1 on tumor cells prior to therapy correlate with clinical efficacy to 
monotherapy or combination therapy?

Does the mutational status of tumor cells (ie KRAS, EGFR) or tumor infectivity (H. pylori, 
HPV) correlate with clinical efficacy to monotherapy or combination therapy?

Can we define distinct pharmacodynamic markers of monotherapy and combination therapy 
in the peripheral compartment?

How does monotherapy or combination therapy alter the activating and negative 
costimulatory molecules on immune cells in the periphery and at the tumor site? Are there
distinct mechanisms of resistance to monotherapy and combination therapy?

Is the intratumoral or peripheral T cell repertoire predictive of response to monotherapy or 
combination therapy?

Does the composition and phenotype of the tumor microenvironment, at baseline, or 
on-treatment, correlate with clinical efficacy?
Peripheral blood and tumor tissue will be collected prior to therapy and at selected timepoints on 
treatment. Additionally, blood and tumor samples of ovarian cancer patients will be evaluated for 
Breast Cancer 1 and 2 (BRCA1/BRCA2) and Homologous Recombinant Deficiency (HRD) gene 
expression. Residual sample material available after completion of the designated analyses may 
be used in the future for identification of additional pharmacodynamic or predictive markers or 
to enhance understanding of disease biology. If biomarker samples are drawn but study drug(s) is 
not administered, samples will be retained. A detailed description of each assay system is 
described below and a schedule of pharmacodynamic evaluations are provided in Table 5.6.8.6-
1.
5.6.2
Biomarker Sampling in Crossover Patients
Mandatory peripheral blood and serum will be drawn if crossing over into Arm N-I from Arm N. 
SCLC subjects from the expansion cohorts under or after Amendment 09 are excluded from the 
crossover option. The timing of these draws will occur on the day of, but prior to, the first N-I 
dose. Biomarker draws do not have to be taken from crossover patients if sampling was 
performed within 7 days of the first combination dose. Follow-up biomarker collections will 
occur according to Table 5.6.8.6-1.
Tumor biopsy samples are optional, but encouraged, and can occur at any point before the first 
dose of N-I and after the last dose of N.
 
 
 
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5.8.3
Demographics and Medical History
At Screening, information regarding subject’s demographics and medical history including date 
of birth, gender, race and ethnicity, general medical history, tobacco use, potential risk factors 
for pulmonary related events, disease diagnosis including diagnosis itself, date of initial 
diagnosis, disease stage at initial diagnosis, cell type, disease classification for SCLC only, 
current disease diagnosis with date and stage, HER-2 status, receptor status, prior surgery, 
radiotherapy, and all prior lines of systemic cancer therapies with agents, start and stop dates, 
best response to the therapy and date of progression after each treatment line will be collected. 
For SCLC and Ovarian cancer subjects, evaluation of Platinum-free interval (PFI) from the 
completion of any platinum-based chemotherapy and subsequent disease progression, and 
Treatment-free-interval (TFI) from the completion of any other cytotoxic or targeted based prior 
treatment line and subsequent disease progression will be collected. For Ovarian Cancer, 
information about BRCA and Homologous Recombinant Deficiency (HRD), if available, will be 
collected.
5.9
Blinded Independent Central Review (BICR)
A Blinded Independent Central Review (BICR) will be performed for randomized subjects in 
selected tumor types to determine RECIST 1.1 response for the analysis of ORR, DOR, and PFS.
Details of the Imaging responsibilities and procedures will be specified in the Imaging charter.
Sites will be informed of quality issues or the need for repeat scanning via queries from the 
central imaging vendor. Results of Central Imaging analysis will not be returned to the site.
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.)
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6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect 

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.) Potential drug induced liver injury (DILI) is also considered an 
important medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. 
(See Section 6.1.1 for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into the 
study. Appropriate documentation is required in these cases
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
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)

hospitalizations for the administration of subsequent anticancer therapy.
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 must be collected that occur during the screening period 
and within 100 days of discontinuation of dosing. Subjects who are randomized but never treated 
with study drug, must have SAEs collected for 30 days from the date of randomization. If 
applicable, SAEs must be collected that relate to any later protocol-specified procedure 
(eg, a follow-up skin biopsy).
The investigator should report any SAE that occurs after these time periods and that is believed 
to be related to study drug or protocol-specified procedure.
An SAE report should be completed for any event where doubt exists regarding its seriousness.
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship 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 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 BMS (or designee) 
using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
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6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects. 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 
as appropriate. All identified nonserious AEs must be recorded and described on the nonserious 
AE page of the CRF (paper or electronic). 
All nonserious adverse events (not only those deemed to be treatment-related) should be 
collected continuously during the treatment period and for a minimum of 100 days following the 
last dose of study treatment.
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which 
were exacerbated by the induction of autoimmunity. Information supporting the assessment will 
be collected on the subject’s case report form.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an SAE 
specified as follows:

Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted

Any laboratory test result abnormality that required the subject to receive specific 
corrective therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of study exposure, including during at 
least 5 half lives after product administration, the investigator must immediately notify the BMS 
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(or designee) Medical Monitor of this event and complete and forward a Pregnancy Surveillance 
Form to BMS (or designee) within 24 hours and in accordance with the SAE reporting 
procedures described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug, after a thorough 
discussion of benefits and risk with the subject.
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 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as SAEs (see Section 6.1.1 for reporting details).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential drug induced liver injury is defined as: 
1. ALT or AST elevation > 3 times upper limit of normal (ULN)
AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND 
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic. 
6.7
Other Safety Considerations
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
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by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly. 
6.8
Safety Assessments
Safety assessments including targeted physical examination, vital signs and oxygen saturation, 
physical measurements including weight and ECOG performance status, and laboratory tests 
including Cell Blood Count (CBC) with differential, Liver Function Tests (LFTs), Blood Urea 
Nitrogen (BUN) or serum urea level, creatinine, albumin, Ca, Mg, Na, K, Cl, LDH, glucose, 
amylase, lipase, TSH (if TSH result is abnormal, subsequent testing of Free T4 and Free T3 is 
required) will be conducted in each treatment cohort as specified in the flow chart in section 5.1.
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
Ipilimumab has been studied in > 13,800 patients in clinical trials while nivolumab has been 
studied in more than 700 patients in clinical trials. The AE profile of nivolumab appears to be 
independent of tumor type. The safety of the combination of nivolumab and ipilimumab has been 
reported in 53 melanoma subjects and the spectrum of adverse events observed among patients 
treated with the concurrent regimen was qualitatively similar to previous experience with 
nivolumab or ipilimumab monotherapy. Adverse events observed with the combination therapy 
were manageable and generally reversible with the use of existing treatment algorithms. In 
addition, this is an open label study. Therefore, a data monitoring committee will not be utilized 
for this Phase 1/2 study.
The subjects’ safety will be monitored on an ongoing basis. Safety conference calls with 
investigators and representatives of the sponsor will be held approximately once a month with 
additional meetings as necessary. The BMS medical monitor is a physician responsible for 
reviewing, on a systematic and continuous basis, the safety of patients on this study. This 
includes a review of serious and non-serious adverse events, which includes all hematological 
and non-hematological events.
In addition, a BMS medical safety team (MST) routinely reviews safety signals across the entire 
nivolumab program including combination studies with ipilimumab. The MST is independent 
from the BMS medical monitor. The MST has the primary responsibility within Bristol-Myers 
Squibb for assessing emerging safety trends, identifying potential safety signals, notifying 
appropriate stakeholders of relevant findings, and implementing risk management plans.
The MST is responsible for reviewing data from all sources including non-clinical studies and 
clinical trials, monitoring the progress of various nivolumab safety support activities, and 
recommending and implementing necessary changes to the safety plan and any other specific 
safety-related activities.
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8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
Sample Size determination in the original protocol
This study comprises a Dose Escalating Safety Evaluation Phase for the Combination Arm, 
followed by a Staged Enrollment for Arm N and Arm N-I. 
In the original protocol, gastric cancer, SCLC, TNBC, and pancreatic cancer are included and the 
Staged Enrollment Part utilizes a modified Simon two-stage design95 with the treatment of 40 
subjects to evaluate whether nivolumab or the combination of nivolumab/ipilimumab yields an 
objective response rate (ORR) that is of clinical interest. In this study, an ORR of 10% or less is 
considered not of clinical value, and an ORR of 25% or greater is considered of strong clinical 
interest. The modified Simon design evaluates the null hypothesis that the true response rate is 
10% versus the alternative hypothesis that the true response rate is > 10%. The 2-stage testing 
within each cohort targets a Type I error rate of 5% and has 80% power to reject the null 
hypothesis if the true response rate is 25%. 
Sample Size determination for bladder cancer cohort
In Amendment 06, the bladder cohort is added. A one stage design with the treatment of 
60 - 100 subjects is used for nivolumab monotherapy and the dose level 2b. These sample sizes 
will provide 90% to 97% power to reject the null hypothesis of 10% response rate if the true 
response rate is 25% with a two-sided Type I error rate of 5%.
In Amendment 14, the dose level 2 arm (nivolumab 1 mg/kg + ipilimumab 3 mg/kg) of the 
bladder cancer cohort is to enroll and treat a total of 92 subjects. A one stage design will be used. 
Based on a 19.6% ORR for nivolumab monotherapy (CA209275), the sample size of 92 in this 
arm will provide 93% power to reject the null hypothesis of 19.6% response rate if the true 
response rate is 35% with a two-sided Type I error rate of 5%.
Sample Size determination for SCLC expansion cohort
In Amendment 09, in addition to the original two-stage design in the SCLC cohort, additional 
SCLC expansion cohort subjects will be randomized in a 3:2 ratio to one of two expansion 
groups: Arm A (150 subjects, nivolumab mono 3 mg/kg q2w) or Arm B (100 subjects, 
nivolumab 1 mg/kg + ipilimumab 3 mg/kg q3w) and will be stratified by number of prior 
treatment lines (1 vs 2 prior chemotherapy regimens).
Based on SCLC data so far observed in this study with an ORR of about 10% for nivolumab 
monotherapy and about 23% for the nivolumab + ipilimumab combination therapy, sample sizes
of N = 150 for nivolumab monotherapy and N = 100 for nivolumab + ipilimumab combination 
therapy (nivolumab 1 mg/kg + ipilimumab 3 mg/kg) will target a Type I error rate of 5% (two-
sided) and will have 78% power to detect the difference between these two arms if the true 
response rates are 10% and 23%, respectively. 
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Sample Size determination for ovarian cancer cohort
Also in Amendment 09, an ovarian cancer cohort is added and a one stage design with the 
treatment of 40 subjects for each combination will be used. These sample sizes will provide 79% 
power to reject the null hypothesis of 10% response rate, if the true response rate is 25% with a 
two-sided Type I error rate of 5%. 
Sample Size determination for the additional pancreatic cancer cohort
A one stage design will be used, with the treatment of 30 subjects with nivolumab 3 mg/kg every 
2 weeks, ipilimumab 1 mg/kg every 6 weeks, and cobimetinib 60 mg po qd 21 days on/7 days 
off. This sample size will provide 70% power to reject the null hypothesis of 10% response rate 
if the true response rate is 25% with a two-sided Type I error rate of 5%.
8.2
Populations for Analyses

All Enrolled Subjects: All subjects who signed an informed consent form and were registered
into the IVRS.

All Assigned Subjects: All subjects who were assigned to the highest tested tolerated dose 
level in the Dose Escalating Safety Evaluation Phase or to any treatment group during the 
Staged Enrollment Phase. 

All Treated Subjects: All subjects who received at least one dose of any study medication.

All PK Subjects: All assigned subjects with available serum time-concentration data.

All Immunogenicity Subjects: All treated subjects with baseline and at least 1 post baseline 
immunogenicity assessment.

All Crossover Subjects: All treated subjects who crossed over from Arm N to Arm N-I.
SCLC subjects from the expansion cohorts under or after Amendment 09 are excluded from 
the crossover option.

All PD-L1 tested subjects: All subjects who had a tumor tissue sample available for 
assessment of PD-L1 expression at baseline.

All treated, PD-L1 tested subjects: All PD-L1 tested subjects who received at least one dose 
of study treatment.

All PD-L1 evaluable subjects: All treated PD-L1 tested subjects with quantifiable PD-L1 
expression.
*Those subjects in the Dose Escalation Safety Evaluation Phase who received at least one dose 
of the highest dose level confirmed for further investigation will be counted as part of the 
required 18 treated subjects for Stage 1. In addition to being included in the All Treated Subjects 
population, those subjects will also be included in the All Dose Escalation Subjects population. 
Those subjects in the Dose Escalation Safety Evaluation Phase who received at least one dose of 
a dose level that was not confirmed for further investigation will not be included in the All 
Treated Subjects population.
8.3
Endpoints
The endpoint definitions apply to all cohorts, unless otherwise specified.
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8.3.1
Primary Endpoint(s)
The primary endpoint is the objective response rate (ORR). The ORR is defined as the number of 
subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) 
divided by the number of treated subjects. The BOR is defined as the best response designation,
as determined by the investigator or BICR for selected tumor types, recorded between the date of
randomization or treatment assignment and the date of objectively documented progression per 
RECIST 1.1 or the date of subsequent anti-cancer therapy, whichever occurs first. CR or PR 
determinations included in the BOR assessment must be confirmed by a second scan no less than 
4 weeks after the criteria for response are first met. For subjects without documented progression 
or subsequent therapy, all available response designations will contribute to the BOR assessment. 
For subjects who continue treatment beyond progression, the BOR should be determined based 
on response designations recorded up to the time of the initial RECIST 1.1-defined progression.
For the SCLC expansion cohort, the estimated difference along with its corresponding p-value of 
ORR assessed by BICR between nivolumab monotherapy and nivolumab / ipilimumab 
combination therapy (nivolumab 1 mg/kg + ipilimumab 3 mg/kg) will be provided. In addition, 
95% CI (two-sided) will also be presented for the estimated difference of ORR between 
nivolumab monotherapy and nivolumab / ipilimumab combination therapy.
Similar methods will be used to summarize ORR for each stratification factor (no p-value will be 
provided).
ORR will be further characterized by the duration of response (DOR) and the magnitude of 
reduction in tumor volume. DOR will be computed for subjects with a BOR of PR or CR and is 
defined as the time from first confirmed response (CR or PR) to the date of the first documented 
tumor progression as determined using RECIST 1.1 criteria or death due to any cause, whichever 
occurs first. For subjects who neither progress nor die, the DOR will be censored using the same 
censoring algorithm as used for PFS in Section 8.3.2. The magnitude of reduction in tumor 
volume is defined as the percent decrease in tumor volume from baseline to nadir, observed up 
until the time of the first documented tumor progression or death.
These measures of response will be interpreted in the context of historical responses observed 
following treatment with approved agents.
8.3.2
Secondary Endpoint(s)
The secondary objective (to assess the safety and tolerability of nivolumab monotherapy, 
nivolumab combined with ipilimumab in subjects with advanced or metastatic tumors, or 
nivolumab combined with ipilimumab and cobimetinib in subjects from the additional pancreatic 
cancer cohort only will be primarily assessed by the rate of treatment-related AEs leading to drug 
discontinuations during the first 12 weeks of treatment. In addition, safety and tolerability will be 
analyzed through the incidence of adverse events, serious adverse events, and specific laboratory 
abnormalities (worst grade) in each cohort. Toxicities will be graded using the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
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PFS is defined as the time from treatment assignment in IVRS to the date of the first documented 
tumor progression, as determined by the investigator or BICR for selected tumor types (per
RECIST 1.1), or death due to any cause, whichever occurs first. Subjects who die without a 
reported prior progression will be considered to have progressed on the date of their death. 
Subjects who did not progress or die will be censored on the date of their last evaluable tumor 
assessment. Subjects who did not have any on-study tumor assessments and did not die will be 
censored on the date they were assigned treatment in the IVRS. Subjects who started anti-cancer 
therapy either prior to death or without a prior reported progression will be censored on the date 
of their last evaluable tumor assessment prior to the initiation of subsequent anti-cancer therapy.
OS is defined as the time between the date of treatment assignment in IVRS and the date of death 
due to any cause. A subject who has not died will be censored at the last known alive date. 
OS will be followed continuously while subjects are on the study drug and every 3 months via
in-person or phone contact after subjects discontinue the study drug.
 
 
 
 
index.
8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Demographic and baseline characteristics will be summarized in all treated subjects by cohort, as 
randomized or assigned, using descriptive statistics.
8.4.2
Efficacy Analyses
8.4.2.1
Primary Endpoint Methods
The efficacy analyses will be performed on the all treated population. ORR will be summarized 
for each cohort by a binomial response rate and corresponding two-sided 95% exact CI using the 
method proposed by Atkinson and Brown96 for cohorts using two-stage design and the Clopper-
Pearson method for cohorts using the one stage design97. 
For SCLC expansion cohort, the estimated difference along with its corresponding p-value of 
ORR assessed by BICR between nivolumab monotherapy and nivolumab/ipilimumab 
combination therapy (nivolumab 1 mg/kg + ipilimumab 3 mg/kg) will also be presented with 
95% CI. Similar methods will be used to summarize ORR for each stratification factor. However 
the p-value will not be provided for each stratification factor.
DOR as determined by the investigator or BICR for selected tumor types will be summarized for
subjects who achieve confirmed PR or CR using the Kaplan-Meier (KM) product-limit method. 
The median value, along with two-sided 95% CI using the Brookmeyer and Crowley method, 
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will also be calculated by cohort. In addition, the percentage of responders still in response at 
different time points (3, 6, and 12 months) will be presented based on the KM plot.
The magnitude of reduction in tumor burden will be summarized descriptively. Immune related 
responses will be summarized descriptively.
8.4.2.2
Secondary Endpoint Methods
PFS and OS will be summarized descriptively using Kaplan-Meier methodology. Median values 
of PFS and OS, along with two-sided 95% CIs using the Brookmeyer and Crowley method, will 
be calculated for each cohort. PFS rates at 6 and 12 months, and OS rates at 12 and 24 months 
will also be estimated. Associated two-sided 95% CIs will be calculated using the Greenwood 
formula. Additional survival analysis may be conducted for up to 5 years beyond analysis of the 
primary endpoint.
 
8.4.3
Safety Analyses
Safety analyses will be performed in all treated subjects. Descriptive statistics of safety will be 
presented using National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0. All on-study AEs, Grade 3-4 AEs, treatment-related AEs, 
Grade 3-4 treatment-related AEs, SAEs, treatment-related SAEs, and AEs leading to 
discontinuation will be tabulated using worst grade per NCI CTCAE v 4.0 criteria by system 
organ class and preferred term. On-study lab parameters including hematology, chemistry, liver 
function, and renal function and Grade 3-4 Lab Abnormalities will be summarized using worst 
grade NCI CTCAE v 4.0 criteria.
8.4.4
Pharmacokinetic Analyses
The nivolumab and ipilimumab concentration data obtained in this study may be combined with 
data from other studies in the clinical development program to develop or refine a population PK 
model. This model will be used to evaluate the effects of intrinsic and extrinsic covariates on the 
PK of nivolumab and ipilimumab and to determine measures of individual exposure (such as 
steady-state peak, trough, and time-averaged concentration). In addition, model determined 
exposures may be used for exposure-response analyses. Results of population PK and exposure 
response-analyses will be reported separately.
.
8.4.6
Outcomes Research Analyses
Subject’s overall health state on a visual analog scale (EQ-VAS) at each assessment time point 
will be summarized using descriptive statistics by treatment arm (N and N-I), as randomized or 
assigned.
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Proportion of subjects reporting problems for the 5 EQ-5D dimensions at each assessment time 
point will be summarized by level of problem and by treatment group, as randomized or 
assigned. Percentages will be based on number subjects assessed at assessment time point.
A by-subject listing of EQ-5D with the problem levels for each of the 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort and anxiety/depression), health state 
(5 dimensions digits combined in a 5-digit number) and EQ-VAS will be provided.
 
 
8.5
Interim Analyses
Data will be reviewed during the Dose Escalation Safety Evaluation Phase to determine the 
maximum tolerated dose level for arm N-I and to make decisions about Stage 2 for each cohort
using Simon’s 2-stage design. The decision to proceed from Stage 1 to Stage 2 will be conducted 
for each tumor type and for each treatment arm independently.
An interim analysis may be conducted after Stage 1, by cohort. This interim analysis may be 
triggered if a “super” response (ie, 8 or more responders out of 18 subjects) is observed or if it is 
necessary in order to make decisions regarding further development. Summaries and listings of 
efficacy and safety will be provided. This interim analysis will not impact the study duration and 
the trial will continue as planned.
Interim analyses may be conducted for supporting internal decision making or for external data 
disclosure purposes by cohort, depending upon the maturity of the data.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations
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Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, and verify 
that the facilities remain acceptable.
In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
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9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product (those supplied by BMS) is maintained at each study site where study 
drug are 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 identification number or batch number 

amount dispensed to and returned by each subject, including unique subject identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for bioavailability/bioequivalence, if applicable 

dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the paper or electronic SAE form and Pregnancy Surveillance form, respectively. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator 
and who is delegated this task on the Delegation of Authority Form For electronic CRFs, review 
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and approval/signature is completed electronically through the BMS electronic data capture tool. 
The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected considering the following criteria:

External Principal Investigator designated at protocol development

National Coordinating Investigator 

Study Steering Committee chair or their designee

Subject recruitment (eg, among the top quartile of enrollers)

Involvement in trial design

Regional representation (eg, among top quartile of enrollers from a specified region or 
country)

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study require approval by BMS prior to publication or presentation 
and must adhere to BMS’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 BMS at the earliest practicable time for review, but 
at any event not less than 30 days before submission or presentation unless otherwise set forth in 
the CTA. BMS 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 BMS 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 
(eg, Investigator Brochure for an unapproved investigational 
product)
Serious Adverse Event
Serious adverse event 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 have caused 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
Term
Definition
AE
adverse event
ACLS
advanced cardiac life support
AI
accumulation index
AI_AUC
AUC Accumulation Index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Cmax
Cmax Accumulation Index; ratio of Cmax at steady state to Cmax after 
the first dose
AI_Ctau
Ctau Accumulation Index; ratio of Ctau at steady state to Ctau after the 
first dose
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
A-V
Atrioventricular
-HCG
beta-human chorionic gonadotrophin
BA/BE
bioavailability/bioequivalence
BC
Breast cancer
BCRA1
Breast cancer type 1
%BE
percent biliary excretion
BICR
Blinded Independent Central Review
BID, bid
bis in die, twice daily
BLQ
below limit of quantification 
BMI
body mass index
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Term
Definition
BMS
Bristol-Myers Squibb
BP
blood pressure
BRt
Total amount recovered in bile
%BRt
Total percent of administered dose recovered in bile
BUN
blood urea nitrogen
C
Celsius
C12
concentration at 12 hours
C24
concentration at 24 hours
Ca++
Calcium
CAV
cyclophosphamide, doxorubicin and vincristine
Cavg
average concentration
CBC
complete blood count
Cexpected-tau
expected concentration in a dosing interval
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
Chloride
CLcr
creatinine clearance
CLD
Dialysate clearance of drug from plasma/serum
CLNR
nonrenal clearance
CLR
renal clearance
CLT
total body clearance
CLT/F (or CLT)
apparent total body clearance
CLT/F/fu or 
CLT/fu
Apparent clearance of free drug or clearance of free if (if IV)
cm
Centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CNS
Central nervous system
CR
Complete response
CRC
Clinical Research Center
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Term
Definition
CRF
Case Report Form, paper or electronic
CT
Computed tomography
Ct
Expected concentration at a certain time, usually at the end of an 
expected future dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctau
Concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
CTLA-4
Cytotoxic T-lymphocyte-associated protein 4
Ctrough
Trough observed plasma concentration
CV
coefficient of variation
CYP
cytochrome p-450
D/C
Discontinue
DCR
Disease control rate
dL
Deciliter
DLT 
Dose limiting toxicity
DOR
Duration of response
DRt
Total amount recovered in dialysate
%DRt
Total percent of administered dose recovered in dialysate
DSM IV
Diagnostic and Statistical Manual of Mental Disorders (4th Edition)
EA
extent of absorption
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
ED
Extensive disease
EDC
Electronic Data Capture
EEG
electroencephalogram
eg
exempli gratia (for example)
EMA
European Medicinal Agency
EOI
End of Infusion
EQ-5D
EuroQol 5 Dimensions Questionnaire
ER
Estrogen receptor
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Term
Definition
ESR
Expedited Safety Report
EU
European Union
F
Bioavailability
Fb
fraction of bound drug
FDA
Food and Drug Administration
FFPE
Formalin-fixed, paraffin-embedded
FI
fluctuation Index ([Cmax-Ctau)/Cavg])
FIGO
Federation of Gynecology and Obstetrics
FOLFIRINOX
combination of 5-FU, leucovorin, irinotecan, oxaliplatin
FRt
total amount recovered in feces
%FRt
total percent of administered dose recovered in feces
FSH
follicle stimulating hormone
%FE
percent fecal excretion
fu
fraction of unbound drug
FU1
Follow-up 1
FU2
Follow-up 2
g
Gram
GC
gas chromatography
GC
Gastric cancer
GCP
Good Clinical Practice
G criteria
adjusted R2 value of terminal elimination phase
GEJ
Gastro-esophageal junction
GEM
Gemcitabine
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
h
Hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCO3-
Bicarbonate
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Term
Definition
HER-2
Human epidermal growth factor receptor 2
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HR
heart rate
HRD
homologous recombinant deficiency
HRT
hormone replacement therapy
IB
Investigator Brochure
IC
Informed Consent
ICD
International Classification of Diseases
ICF
Informed consent form
ICH
International Council for Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IFN
Interferon
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
irCR
Immune related complete response
irPR
Immune related partial response
irPD
Immune related progression
IU
International Unit
IV
Intravenous
K
slope of the terminal phase of the log concentration-time curve
K3EDTA
potassium ethylenediaminetetraacetic acid
K+
Potassium
kg
Kilogram
KM
Kaplan-Meier
z
terminal disposition rate constant
L
Liter
LC
liquid chromatography
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Term
Definition
LD
Limited disease
LDH
lactate dehydrogenase
LFT
Liver function test
ln
natural logarithm
Lz_Start
The time point starting the log-linear elimination phase defining the 
terminal half life
Lz_End
The time point ending the log-linear elimination phase defining the 
terminal half life
Lz_N
Number of time points in the log-linear elimination phase defining the 
terminal half life
MST
medical safety team
mg
Milligram
Mg++
Magnesium
MIC
minimum inhibitory concentration
min
Minute
mIU/ml
Milli international units per millimeter
mL
Milliliter
mmHg
millimeters of mercury
mOS
Median overall survival
mRCC
Metastatic renal cell carcinoma
MR_AUC(0-T)
Ratio of metabolite AUC(0-T) to parent AUC(0-T), corrected for 
molecular weight
MR_AUC(INF)
Ratio of metabolite AUC(INF) to parent AUC(INF), corrected for 
molecular weight
MR_AUC(TAU)
Ratio of metabolite AUC(TAU) to parent AUC(TAU), corrected for 
molecular weight
MR_Cmax
Ratio of metabolite Cmax to parent Cmax, corrected for molecular 
weight
MR_Ctau
Ratio of metabolite Ctau to parent Ctau, corrected for molecular weight
MRI
Magnetic resonance imaging
MRT
mean residence time
MS
mass spectrometry
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Term
Definition
MTD
maximum tolerated dose
g
Microgram
N
number of subjects or observations
N
Nivolumab monotherapy
N-I
Nivolumab in combination with Ipilimumab
Na+
Sodium
N/A
not applicable
NCCN
National Comprehensive Cancer Network
NCI CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse 
Events
ng
Nanogram
NIMP
non-investigational medicinal products 
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
Non-small cell lung cancer
ORR
Overall response rate
OS
Overall survival
PAC
Paclitaxel
PARP
Poly (ADP-ribose) polymerase
pAUCe
Extrapolated partial AUC from last quantifiable concentration to infinity
Pb
percent of bound drug
PBMC
Peripheral blood mononuclear cell
PC
Pancreatic cancer
pCR
Complete pathological response
PD
Pharmacodynamics
PD-1
Programmed death 1
PDL-1
Programmed cell death 1 ligand 1
PE
Physical Exam
PE
Platinum plus etopiside
PFI
platinum-free interval
PFS
Progression Free Survival
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Term
Definition
PK
Pharmacokinetics
PO
per os (by mouth route of administration)
PR
Partial response
PR
Progesterone receptor
PS
Performance status
PT
prothrombin time
PTT
partial thromboplastin time
Pu
percent of unbound drug
Q2W
Every two weeks
Q3W
Every three weeks
QC
quality control
QD, qd
quaque die, once daily
R2
coefficient of determination
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RT-PCR
Reverse transcription-polymerase chain reaction
SAE
serious adverse event
SCLC
Small cell lung cancer
SD
stable disease
SD
standard deviation
SOC
Standard of care
SOP
Standard Operating Procedures
sp.
Species
Subj
Subject
t
Temperature
T
Time
TAO
Trial Access Online, the BMS implementation of an EDC capability
TEN
toxic epidermal necrolysis
TFI
Treatment-free-interval
T-HALF
Half life
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Term
Definition
T-HALFeff_AUC
Effective elimination half-life that explains the degree of AUC 
accumulation observed
T-HALFeff_Cmax
Effective elimination half-life that explains the degree of Cmax 
accumulation observed)
TID, tid
ter in die, three times a day
Tmax, TMAX
time of maximum observed concentration
TNBC
Triple negative breast cancer
TPC
Treatment of physician’s choice
TR_AUC(0-T)
AUC(0-T) treatment ratio
TR_AUC(INF)
AUC(INF) treatment ratio
TR_Cmax
Cmax treatment ratio
UR
urinary recovery
%UR
percent urinary recovery
URt
total amount recovered in urine
US
United States
%URt
total percent of administered dose recovered in urine
UV
Ultraviolet
Vss/F (or Vss)
apparent volume of distribution at steady state
Vz
Volume of distribution of terminal phase (if IV and if multi-exponential 
decline)
W
Washout
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
x g
times gravity
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APPENDIX 1
PERFORMANCE STATUS SCALES
STATUS
SCALES
STATUS
KARNOFSKY
ZUBROD-
ECOG-WHO
Normal, no complaints
100
0
Normal activity
Able to carry on normal activities Minor 
signs or symptoms of disease
90
0
Symptoms, but fully 
ambulatory
Normal activity with effort
80
1
Cares for self. Unable to carry on 
normal activity or to do active work
70
1
Symptomatic, but in bed 
< 50% of the day.
Requires occasional assistance, but able 
to care for most of his needs
60
2
Requires considerable assistance and 
frequent medical care
50
2
Needs to be in bed > 50% of 
the day, but not bedridden
Disabled. Requires special care and 
assistance
40
3
Severely disabled. Hospitalization 
indicated though death non imminent
30
3
Very sick. Hospitalization necessary. 
Active supportive treatment necessary
20
4
Unable to get out of bed
Moribund
10
4
Dead
0
5
Dead
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APPENDIX 2
MANAGEMENT ALGORITHMS
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APPENDIX 3
RECIST 1.1
Changes in tumor measurements and tumor responses will be assessed by the investigator using 
the RECIST 1.1 (Response Evaluation Criteria in Solid Tumors) criteria. (Eisenhauer, et al 
2009.)
Source:  Eisenhauer et al New response evaluation criteria in solid tumours: Revised RECIST 
guideline (version 1.1), European Journal of Cancer, 2009, Vol. 45, p 228-247
1
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
To assess objective response or future progression, it is necessary to estimate the overall tumor
burden at baseline and 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 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows:
1.1
Measurable lesions
Measurable lesions must be 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 by CT/MRI scan - (CT/MRI scan slice thickness no greater than 5 mm)

10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable)

20 mm by chest x-ray

Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.
1.2
Non-measurable lesions

All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with 10 to < 15 mm short axis), as well as truly non-measurable lesions.  

Lesions considered truly 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.
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1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions

Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.

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 selection as target lesions.
1.3.3
Lesions with prior local treatment
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 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 28 days before the 
beginning of the treatment.
1.4.2
Method of assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
1.4.2.1
CT/MRI scan
CT/MRI is the best currently available and reproducible method to measure lesions selected for 
response assessment. Measurability of lesions on CT/MRI scan is based on the assumption that 
CT/MRI slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness.
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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 
aerated lung.
1.4.2.3
Clinical lesions 
Clinical lesions will only be considered measurable when they are superficial and 10 mm 
diameter as assessed using calipers. For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is suggested. As previously noted, 
when lesions can be evaluated by both clinical 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 not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. 
1.4.2.5
Endoscopy, laparoscopy
The utilization of these techniques for objective tumor evaluation is not advised.
1.4.2.6
Tumor markers 
Tumor markers alone cannot be used to assess objective tumor response.  
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 to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should lend themselves to reproducible repeated
measurements.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted below, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
2.1.1
Lymph nodes
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
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15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
Nodes that have a short axis < 10 mm are considered 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-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’. 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’).
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 < 10 mm.
Partial Response (PR):  At least a 30% decrease in the sum of diameters of target lesions,
taking as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression).
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
3.1.1
Special notes on the assessment of target lesions
3.1.1.1
Lymph nodes
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
Nodes that have a short axis <10 mm are considered 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. 2 mm). If the radiologist is 
able to provide an actual measurement, that should be recorded, even if it is below 5 mm.
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However, when such a lesion becomes difficult to assign an exact measure to then:

if it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm. 

if the lesion is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned (note: in case of a lymph node believed to be present and 
faintly seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well). This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).
3.1.1.3
Target lesions that split or coalesce on treatment

When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should 
be added together to calculate the target lesion sum. 

As lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced 
such that they are no longer separable, the vector of the longest diameter in this instance 
should be the maximal longest diameter for the ‘coalesced lesion’.
3.2
Evaluation of non-target lesions
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis).
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD):  Unequivocal progression of existing non-target lesions. (Note: the 
appearance of one or more new lesions is also considered progression).
3.2.1
Special notes on assessment of non-target lesions
The concept of progression of non-target disease requires additional explanation as follows:
3.2.1.1
When the subject also has measurable disease

To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. 

A modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to 
quality for unequivocal progression status.
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3.2.1.2
When the subject has only non-measurable disease

To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening such that the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. 

A modest ‘increase’ in the size of 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 tumor burden representing 
an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, 
an increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as ‘sufficient to require a change in therapy’.

If ‘unequivocal progression’ is seen, the subject should be considered to have had overall PD 
at that point. 
3.2.1.3
Tumor markers
Tumor markers alone cannot be used to assess objective tumor responses. If markers are initially 
above the upper normal limit, however, they must normalize in order for a subject to be 
considered as having attained a complete 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 not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the subject who has visceral disease at baseline and while on study has a CT or MRI brain scan
ordered 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, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan.
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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 might be a sign of PD 
based on a new lesion. However, other reasons for newly detected lesions with increased 
FDG-PET uptake, such as inflammatory lymphnodes, should be taken into consideration.

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 positive FDG-
PET scan).

If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD.

Other reasons for newly detected lesions with increased FDG-PET uptake, such as 
inflammatory lymphnodes, should be taken into consideration.
4
RESPONSE CRITERIA
4.1
Time point response
A response assessment should occur at each time point specified in the protocol.
For subjects who have measurable disease at baseline Table 1 provides a summary of the 
overall response status calculation at each time point.
Table 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 or not all 
evaluated
No
PR
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Table 1:
Time point response: subjects with target (+/– non-target) disease.
Target lesions
Non-target lesions
New lesions
Overall response
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.
For subjects who have non-measurable (therefore non-target) disease only, Table 2 is to be 
used.
Table 2:
Time point response: Subjects with non-target disease only
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is 
not advised.
CR = complete response, PD = progressive disease, and NE = not evaluable.
4.1.1
Missing assessments and not evaluable designation
When no imaging/measurement is done at all at a particular time point, the subject is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
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assessment, the case is also considered NE at that time point, unless a convincing argument can 
be made that the contribution of the individual missing lesion(s) would not have changed the 
assigned time point response.
4.1.2
Confirmation of Scans and External Evaluation

Verification of Response: Confirmation of response (CR or PR) is required. Confirmed CR 
or PR will be claimed only if the criteria for each are met at a subsequent timepoint 
(minimum 4 weeks after criteria for an objective response are first met).

Verification of Progression: Progression of disease should be verified in cases where 
progression is equivocal. If repeat scans confirm PD, then progression should be declared 
using the date of the initial scan. If repeat scans do not confirm PD, then the subject is 
considered not to have progressive disease per RECIST 1.1.

External Evaluation of scans: For all subjects, BMS will request the transfer of anonymized 
scans for a BMS internal or external evaluation through a third party. For tumor types where 
data from study CA209-032 will potentially be used for future NDA submissions, BMS will 
request the transfer of anonymized scans from all subjects with this tumor type for a BMS 
internal or external evaluation through a third party.
4.2
Best overall response: All timepoints
The best overall response is determined once all the data for the subject is known. It is defined as 
the best response designation, as determined by the investigator, recorded between the date of 
first treatment and the date of objectively documented progression per RECIST1.1 or the date of 
subsequent therapy, whichever occurs first. For subjects without documented progression or 
subsequent therapy, all available response designations will contribute to the BOR assessment. 
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.
Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point (minimum 4 weeks after criteria of objective response are first met). In 
this circumstance, the best overall response can be interpreted as in Table 3.
Table 3:
Best overall response when confirmation of CR and PR IS required.
Overall response
Overall response
BEST overall response
First time point
Subsequent time 
point
CR
CR
CR
CR
PR
SD, PD or PRa
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Table 3:
Best overall response when confirmation of CR and PR IS required.
Overall response
Overall response
BEST overall response
First time point
Subsequent time 
point
CR
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
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.
For purposes of this study, the minimum scan time from baseline for determination of SD will be 
6 weeks.
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).
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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).
4.3.3
Immune related Response Criteria
Immune related response criteria using unidimensional measurements may be used to describe 
tumor shrinkage following RECIST defined disease progression Appendix 3. The methodology 
is the same as described above for RECIST except:

New lesions do not automatically denote disease progression

The measurement of longest diameter of new measurable lesions are in included in the sum 
of the measurements of the original target lesions.
Best immune related responses, for subjects who have progression followed by tumor shrinkage 
are classified as irCR (disappearance of all lesions) or irPR (30% reduction from baseline).
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APPENDIX 4
DEFINITION OF PRIOR RESPONSE TO PLATINUM-BASED 
CHEMOTHERAPY IN SCLC
Platinum sensitive: Progression free interval 90 days after completion of any platinum-based 
chemotherapy.
Platinum resistant: Progression free interval < 90 days after completion of any platinum-based
chemotherapy.
Platinum refractory: Progression during platinum-based chemotherapy.
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APPENDIX 5
DEFINITION OF PRIOR RESPONSE TO PLATINUM-BASED 
CHEMOTHERAPY IN OVARIAN CANCER
Platinum-sensitive: Relapse > 6 months after stop of any platinum-based chemotherapy.
Platinum-resistant: Relapse > 1 to 6 months after stop of any platinum-based chemotherapy.
Platinum-refractory: Relapse on or within 1 month after stop of any platinum-based 
chemotherapy.
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APPENDIX 6
ROYAL MARSDEN PROGNOSTIC SCORE
Source: Arkenau HT, Barriuso J, Olmos D, Ang JE, et al. Prospective Validation of a Prognostic 
Score to Improve Patient Selection for Oncology Phase I Trials. J Clin Oncol. 2009;27:2692-
2696
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APPENDIX 7
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP

Premenarchal

Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female

A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 
40 mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. 

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/mL at any time during the washout period, the woman can be considered 
postmenopausal.
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CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD 
BEARING POTENTIAL
One of the highly effective methods of contraception listed below is required during study 
duration and until the end of relevant systemic exposure, defined as 5 months after the end of 
study treatment in the female participant.
Local laws and regulations may require use of alternative and/or additional contraception 
methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 

oral 

intravaginal 

transdermal 

Progestogen-only hormonal contraception associated with inhibition of ovulationb 

oral 

injectable 
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b

Intrauterine device (IUD)c

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 

Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.

It is not necessary to use any other method of contraception when complete abstinence is 
elected. 

WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in the protocol. 

Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
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NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical 
studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence 
that the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative 
methods of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.

Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.

Male participants are required to use a condom for study duration and until the end of 
relevant systemic exposure, defined as 7 months after the end of treatment in the male 
participant.

Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end 
of treatment in the male participant.

Male participants with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile vaginal intercourse or use a male condom during each episode of penile 
penetration during the treatment and until 7 months after the end of treatment. 

Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of treatment.
Local laws and regulations may require use of alternative and/or additional contraception 
methods.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 6.4 and Section 6.1.1 on Serious Adverse Event 
Collection and Reporting.
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Date: 23-Aug-2019
2
be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 08
23-Aug-2019

Updated personnel with Medical Monitor

Added live/attenuated vaccines and complementary medications
(eg, herbal supplements) to Prohibited and/or Restricted Treatments

Clarified tumor assessment language

Updated Appendix 2 (Management Algorithms) with addition of
myocarditis AE management algorithm to reflect update in the
Nivolumab IB

Added survival visits time window (from Administrative letter 5, dated
27-Aug-2018)
Administrative 
Letter 05
27-Aug-2018
Updated survival visit information
Administrative 
Letter 04
31-Jan-2018
Updated study personnel
Administrative 
Letter 03
11-Jan-2018
Corrected Date of Issue in Document History for Amendment 10
Administrative 
Letter 02
18-Apr-2017
Updated study personnel
Revised 
Protocol 07
10-Aug-2016
Incorporates Amendment 12
Amendment 12
10-Aug-2016

Changed the primary objective for the expansion SCLC cohort to
require evaluation by BICR.

Removed the limitation of enrolling subjects with 1 or 2 prior lines of
therapy in the same fixed proportion of 50% for each subgroup.

Added permission to use palliative radiation therapy to other non-
target lesions

Added permission to use surgical resection or stereotactic radiotherapy
following initial response or long-term stable disease

Limited PK and immunogenicity samples collection up to 2 years

Updated Appendix 2 (Management Algorithms) to reflect updates in
the nivolumab IB.

Added Appendix 6 (Methods of Contraception) to reflect updates in
the nivolumab IB.
Revised 
Protocol 06
18-Nov-2015
Incorporates Amendment 11
Amendment 11
18-Nov-2015
•
Clarification regarding the local lab assessment timing was added.
•
For Ovarian Cancer cohort, specification of minimum tissue sample
collection for ovarian cancer due to the fact that additional analyses of
Homologous Recombination Deficiency (HRD) status and Breast
Cancer genes 1 and 2 (BRCA1 and BRCA2) mutation status will be
conducted in this cohort.
•
For SCLC expansion cohort, exact language regarding number of prior
treatment lines added for consistency with Section 3.1.5 and the study
synopsis.
•
Specification of the crossover option: This option refers only to the
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Document
Date of Issue
Summary of Change
glucose controlling agents, may undergo retreatment. A recurrence of the 
endocrinopathy event under ongoing physiologic hormone replacement 
therapy appears to be unlikely what justifies a retreatment with potential 
therapeutic benefit.
• The definition of the all immunogenicity population was changed in
order to align it with the core safety SAP for the Nivolumab program.
Other minor changes in the populations for analyses were made in order
to align it with the SAP for 032.
• The interim analysis section was updated to allow for IAs based on either
a “super” response or if it is necessary to make decisions regarding
further development (eg, the SCLC cohort).
Revised 
Protocol 01
11-Dec -2013
Incorporates Amendment 05
Amendment 05
11-Dec-2013
Study Design:
• Clarification on need for subject safety follow up before dose escalation
and staggered enrollment for Dose Cohort Level 2.
• Clarification on number of subjects with objective response and number
of enrolled subjects before proceeding from Stage 1 to Stage 2.
Eligibility Criteria
• Clarified wording that subjects with Breast Cancer, Gastric or Gastro-
Esophageal Junction Carcinoma, or SCLC must have progressive or
refractory disease at study entry.
• Adjusted eligibility, treatment delay and discontinuation criteria for
subjects with lipase or amylase > 1.5 ULN: Subjects with asymptomatic
elevations in amylase or lipase not associated with symptoms, clinical
manifestations, or radiographic sings of pancreatitis are eligible. Based
on clinical experience in ongoing studies with nivolumab and
ipilimumab, asymptomatic elevations of amylase or lipase have not been
proven to have to have independent clinical consequence or predict for
development or severity of pancreatitis. A wide variation of
asymptomatic elevations in amylase or lipase can occur on a day-to-day
basis, limiting the utility of interpreting the amylase or lipase elevations
in isolation.
• Clarifications on eligibility for women of childbearing potential and
effective methods of contraception.
• Clarification on eligibility of subjects with prior malignancy not
interfering with the primary and secondary study endpoints.
.
Study procedures
• Implementation of time windows for study visits and biomarker
assessments.
In addition, inconsistencies within the protocol for mandatory tumor 
biopsies were resolved.
Original 
Protocol
10-Jul-2013
Not applicable
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OVERALL RATIONALE FOR REVISED PROTOCOL 08
This revised protocol provides clarity on the tumor assessments during treatment and follow-up. 
Additional changes were made for prohibited and restricted treatments. The changes apply for all 
participants in the study.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 08
Section Number & Title
Description of Change
Brief Rationale
Section 3.4.1 Prohibited and/or 
Restricted Treatments
Section 3.4.2.3 Permitted 
Therapy
Updated language for permitted therapy and 
additional prohibited and/or restricted 
treatments were added: 

Any complementary medications (eg,
herbal supplements or traditional Chinese 
medicines) intended to treat the disease 
under study. Such medications are allowed 
if they are used as supportive care.  

Any live / attenuated vaccine (eg varicella,
zoster, yellow fever, rotavirus, oral polio
and measles, mumps, rubella (MMR))
during treatment and until 100 days post
last dose.
Prohibited and/or restricted 
treatments were updated to 
align with program 
standards for safety.
Section 5 Study Assessments 
and Procedures
On-study Assessment tables:
Table 5.1-2
Table 5.1-3
Table 5.1-4
Table 5.1-5
Section 5.3.1 Imaging 
Assessment for the Study
Tumor assessment language was added to 
tables:
Additionally, with the exception of crossover 
participants, tumor assessments will not be 
required upon initiation of subsequent anti-
cancer therapy.
On-treatment tables were 
updated to provide clarity 
that tumor assessments are 
not required after subjects 
receive subsequent anti-
cancer therapy.  
Appendix 2
Management Algorithms were updated to 
include AE management for myocarditis
Appendix aligns with 
revised Nivolumab IB for 
safety.
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SYNOPSIS
Clinical Protocol CA209032
Protocol Title: A Phase 1/2, Open-label Study of Nivolumab Monotherapy or Nivolumab combined with 
Ipilimumab in Subjects with Advanced or Metastatic Solid Tumors
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s):

Nivolumab monotherapy administered IV over 60 minutes at 3 mg/kg every 2 weeks until progression
or

Nivolumab administered IV over 60 minutes at 1 mg/kg combined with ipilimumab administered IV over
90 minutes at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab administered IV over 60 minutes at
3 mg/kg every 2 weeks until progression.
or

Nivolumab administered IV over 60 minutes at 1 mg/kg combined with ipilimumab administered IV over
90 minutes at 3 mg/kg every 3 weeks for 4 doses followed by nivolumab administered IV over 60 minutes at
3 mg/kg every 2 weeks until progression.
or

Nivolumab administered IV over 60 minutes at 3 mg/kg combined with ipilimumab administered IV over
90 minutes at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab administered IV over 60 minutes at
3 mg/kg every 2 weeks until progression.
or

Nivolumab administered IV over 60 minutes at 3 mg/kg every 2 weeks combined with ipilimumab administered
IV over 90 minutes at 1 mg/kg every 6 weeks until progression.
Study Phase: 1/2
Research Hypothesis: Treatment with nivolumab monotherapy or nivolumab combined with ipilimumab will have 
clinical activity in subjects with advanced or metastatic tumors.
Objectives:
Primary Objective
SCLC Expansion Cohort:

To compare the objective response rate (ORR) as assessed by a Blinded Independent Central Review (BICR)
for nivolumab monotherapy versus nivolumab combined with ipilimumab (nivolumab 1 mg/kg +
ipilimumab 3 mg/kg).
Other Cohorts:

To evaluate the objective response rate (ORR) of nivolumab monotherapy or nivolumab combined with
ipilimumab in subjects with advanced or metastatic tumors. ORR will be assessed by a BICR in selected tumor
types.
Secondary Objective

To assess the safety of nivolumab monotherapy or nivolumab combined with ipilimumab in subjects with
advanced or metastatic tumors.

To assess Overall Survival (OS), OS-rate, Progression Free Survival (PFS), PFS-rate, and Duration of Response
(DOR) with nivolumab monotherapy or nivolumab combined with ipilimumab in subjects with advanced or
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Figure 1:
Study Design for Each Tumor Type
*dose level 1 (N1 mg/kg Q3W +I1 mg/kg Q2W) and dose level 2 (N1 mg/kg Q3W + I3 mg/kg Q2W); ** dose level
2b (N3 mg/kg Q3W + I1 mg/kg Q2W); *** dose level 2c (N3 Q2W + I1 Q6W
Dose-escalating Safety Evaluation Phase for Combination Arm: Although the regimen currently used in the 
phase 3 melanoma study, nivolumab 1 mg/kg IV + ipilimumab 3 mg/kg, was expected to also be tolerable in the 
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tumors studied here, an initial dose-escalating safety evaluation for the combination arms was conducted with GC, 
PC, TNBC, or SCLC (described in protocol Section 3.1.3). The BC cohort was added to this protocol following the 
completion of the safety evaluations in GC, PC, TNBC, and SCLC at dose level 1 (nivolumab 1 mg/kg, ipilimumab 
1 mg/kg) which did not reveal safety concerns. Thereby the starting dose level for the BC cohort was dose level 2
(nivolumab 1 mg/kg, ipilimumab 3 mg/kg). Six BC patients were initially randomized to Dose Level 2, after which 
enrollment to Dose Level 2b (nivolumab 3 mg/kg, ipilimumab 1 mg/kg) began.
Enrollment to Stage 1 for Arm N occurred in parallel to the safety evaluation for Arm N-I.
Two Stage Design: GC, PC, TNBC, or SCLC Arms N and N-I will follow a two-stage design to test whether 
nivolumab monotherapy or nivolumab combined with ipilimumab yields an objective response rate (ORR) that is of 
clinical interest in the investigated tumor types. For each tumor type, only treatment arms which meet an ORR 
threshold will proceed from Stage 1 to Stage 2 (described in protocol Section 3.1.4). Enrollment to Stage 2 in a 
given treatment arm can continue even if the other treatment arm is still in Stage 1.
Table 1:
Efficacy criteria to proceed from Stage 1 to Stage 2
Efficacy criteria
Next Step
2 or more of 18 subjects in a given arm have confirmed PR or CR
Go into Stage 2
1 or no of 18 subjects in a given arm have confirmed PR or CR.
No Go into Stage 2
For Stage 2, upon completion of enrollment of the initial 40 subjects, additional subjects may be assigned into Arm 
N and Arm N-I up to a total of 100 subjects (including those assigned in Stage 1) in each treatment arm of the given 
tumor type. For tumor types where nivolumab monotherapy or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg 
proceeded to Stage 2, assessment of Dose Level 2b in Stage 2 (nivolumab 3 mg/kg + ipilimumab 1 mg/kg, n=up to 
70 subjects) may be initiated for that tumor type. For SCLC, an additional 250 subjects (second- or third-line) will 
be randomized in a 3:2 ratio to one of the 2 expansion groups: nivolumab 3 mg/kg every 2 weeks or nivolumab
1 mg/kg + ipilimumab 3 mg/kg every 3 weeks for 4 cycles followed by nivolumab 3 mg/kg.
Modified Design for Bladder Cancer Cohort:
Bladder arms N and N-I (Dose Levels 2 and 2b) will be conducted as a One Stage Design with the treatment of 
26-105 subjects in each arm. The Safety Evaluation Phase for the N-I arm will start at Dose Level 2 (nivolumab
1 mg/kg, ipilimumab 3 mg/kg) and will evaluate safety and tolerability after the first 6 randomized subjects.
Following the N-I safety evaluation phase, Dose Level 2 will enroll 26 subjects and 2b will enroll up to a total of
105 subjects. Based on the safety evaluations thus far on study, no dose escalation phase is necessary for bladder
cohort N-I Dose Level 2b (nivolumab 3 mg/kg, ipilimumab 1 mg/kg).
Modified Design for Ovarian Cancer Cohort:
Ovarian arm N-I (Dose Levels 2, 2b and 2c) will be conducted as a One Stage Design with the treatment of 
40 subjects in each arm. Due to the low risk of development of new safety signals on the combination arms no safety 
evaluation phase will be employed. Ovarian cancer subjects will be followed for related toxicities and decisions to 
stop treatment will be made on an ongoing basis.
SCLC expansion:
SCLC cohorts Arm N and Arm N-I met the pre-specified safety and efficacy criteria and proceeded to Stage 2. 
Based on an interim data review, disease control rates (SD + PR + CR) of 36% and 57% for Arms N and N-I, 
respectively, were estimated. In order to further investigate nivolumab and nivolumab combined with ipilimumab 
activity in specific SCLC subpopulations, the SCLC expansion cohorts will enroll additional subjects based on 
response to prior treatment and the number of previous therapies. Up to 250 second or third line subjects will be 
randomized in a 3:2 ratio to one of 2 expansion groups: Arm A (150 subjects treated with nivolumab 3 mg/kg every 
2 weeks (Q2W)) or Arm B (100 subjects treated with nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks 
(Q3W) for 4 cycles followed by nivolumab 3 mg/kg (Q2W) and will be stratified for number of prior treatment lines 
(1 vs 2 prior chemotherapy regimens). The crossover option refers only to the original cohorts and not the new 
cohorts enrolled under or after Amendment 09 implementation.
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Crossover for subjects in Arm N: Subjects in Arm N may crossover to Arm N-I if all of the following criteria are 
met: 

The Safety Evaluation Phase for the N-I regimen has been completed and at least 6 subjects have been exposed
to the dose level used for Stage 1 of the N-I regimen. In case Dose Level 2b has been activated and the safety
assessment completed, subjects for cross over will be assigned to Dose Level 2b.

Subject has confirmed radiologic disease progression (investigator-assessed RECIST 1.1 defined progression
confirmed at least 4 weeks after the initial tumor assessment showing progression) in the absence of clinical
deterioration. For subjects with clear evidence of new or progressing brain metastases a confirmation is not
required. These subjects may proceed with brain radiation therapy and after having completed the radiation
therapy a cross over to Arm N-I can be considered.

Subjects with rapidly progressing tumors under nivolumab monotherapy may undergo radiation treatment first
before initiation of the cross over after discussion between the sponsor and investigator.

Subject has not experienced nivolumab related adverse events leading to permanent discontinuation.

Subject is not continuing to derive any clinical benefit from nivolumab single agent therapy as assessed by the
investigator which would allow continuation of nivolumab monotherapy.

Subject is not a SCLC patient enrolled based on the Amendment 09 expansion.

The individual case must be discussed with the medical monitor prior to cross over.
Subjects crossing over to Arm N-I will start treatment at Day 1 Week 1 as described for subjects originally 
randomized to Arm N-I. Subjects who cross over and subsequently have an objective response in Arm N-I will not 
be considered in the decision making for Arm N I proceeding to Stage 2.
Study Population:
Key Inclusion Criteria

Subjects with histologically confirmed locally advanced or metastatic disease of one of the following tumor
types and who meet the eligibility criteria defined in Section 3.4.1:
o
Triple Negative Breast Cancer
o
Gastric Cancer
o
Pancreatic Cancer
o
Small Cell Lung Cancer
o
Bladder Cancer
o
Ovarian Cancer

Subjects must have measurable disease by CT or MRI per RECIST 1.1 criteria (radiographic tumor assessment
must be performed within 28 days prior to first dose)

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Key Exclusion Criteria

Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if these have
been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks
after treatment is complete and within 28 days prior to first dose of study drug administration. There must also
be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone
equivalents) for at least 2 weeks prior to study drug administration.

Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus,
residual hypothyroidism due to autoimmune condition only requiring hormone replacement, or conditions not
expected to recur in the absence of an external trigger are permitted to enroll.
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab

Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone
equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or
topical steroids, and adrenal replacement doses are permitted in the absence of active autoimmune disease.

Prior therapy with experimental anti-tumor vaccines; any T cell co-stimulation or checkpoint pathways, such as
anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, including ipilimumab; or other
medicines specifically targeting T cell is also prohibited.
Study Assessments:
Tumor assessments
The primary endpoint of this study, ORR, is based on tumor assessments at baseline and then at 6 weeks from first 
dose. Tumor assessments continue every 6 weeks for the first 24 weeks and every 12 weeks thereafter while on 
treatment or on treatment hold for any reason until disease progression (investigator-assessed RECIST 1.1-defined 
progression) or treatment discontinuation, except for subjects treated beyond progression or who discontinued 
treatment for other reasons than PD.
Statistical Considerations:
Sample Size Determination
Sample size determination in the original protocol
This study comprises a Dose Escalating Safety Evaluation Phase for the Combination Arm, followed by a Staged 
Enrollment for Arm N, and Arm N-I. 
In the original protocol, gastric cancer, small cell lung cancer, triple negative breast cancer, and pancreatic cancer 
are included and the Staged Enrollment Part utilizes a modified Simon two-stage design with the treatment of 
40 subjects to evaluate whether nivolumab, or the combination of nivolumab/ipilimumab yields an objective 
response rate (ORR) that is of clinical interest. In this study, an ORR of 10% or less is considered not of clinical 
value, and an ORR of 25% or greater is considered of strong clinical interest. The modified Simon design evaluates 
the null hypothesis that the true response rate is 10% versus the alternative hypothesis that the true response rate is 
> 10%. The 2-stage testing within each cohort targets a Type I error rate of 5% and has 80% power to reject the null
hypothesis if the true response rate is 25%.
Sample size determination for bladder cancer cohort
In Amendment 06, the bladder cohort is added. A one stage design with the treatment of 60-100 subjects is used. 
These sample sizes provide 90% to 97% power to reject the null hypothesis of 10% response rate if the true response 
rate is 25% with a two-sided Type I error rate of 5%.
Sample size determination for SCLC expansion cohort
In Amendment 09, in addition to the original two-stage design of SCLC subjects, additional SCLC expansion cohort 
subjects will be randomized in a 3:2 ratio to one of 2 expansion groups: Arm A (150 subjects, nivolumab mono) or 
Arm B (100 subjects, nivolumab 1 mg/kg + ipilimumab 3 mg/kg) and will be stratified for number of prior treatment 
lines (1 vs 2 prior chemotherapy regimens). 
Based on SCLC data so far observed in this study with an ORR of about 10% for nivolumab monotherapy and about 
23% for nivolumab / ipilimumab combination therapy, sample sizes of N = 150 for nivolumab monotherapy and 
N = 100 for nivolumab / ipilimumab combination therapy (nivolumab 1 mg/kg + ipilimumab 3 mg/kg) will target a 
Type I error rate of 5% (two-sided) and will have 78% power to detect the difference between these two arms, if the 
true ORR rates are 10% and 23%, respectively.
Sample size determination for ovarian cancer cohort
Also in Amendment 09, an ovarian cancer cohort is added and a one stage design with the treatment of 40 subjects 
for each arm is used. These sample sizes will provide 79% power to reject the null hypothesis of 10% response rate 
if the true response rate is 25% with a two-sided Type I error rate of 5%.
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CA209032
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nivolumab / ipilimumab
Primary Endpoint:
Objective Response Rate
Analyses:
ORR will be summarized for each cohort by a binomial response rate and corresponding two-sided 95% exact CI 
using the method proposed by Atkinson and Brown for cohorts using a two-stage design and the Clopper-Pearson 
method for cohorts using a one-stage design.
For SCLC expansion cohort, the estimated difference including 95% CI of the estimated difference along with its 
corresponding p-value of ORR assessed by BICR between nivolumab monotherapy and nivolumab/ipilimumab 
combination therapy (nivolumab 1 mg/kg + ipilimumab 3 mg/kg) will be presented with 95% CI. Similar methods 
will be used to summarize ORR for each stratification factor. However, p-value will not be provided for each 
stratification factor.
DOR as determined by the investigator or BICR for selected tumor types will be summarized for subjects who 
achieve confirmed PR or CR using the Kaplan-Meier (KM) product-limit method. Median values of DOR, along 
with two-sided 95% CI using the Brookmeyer and Crowley method will also be calculated by cohort. In addition, 
the percentage of responders still in response at different time points (3, 6, and 12 months) will be presented based 
on the KM plot.
The magnitude of reduction in tumor burden will be summarized descriptively. Immune related responses will be 
summarized descriptively.
Secondary Endpoints:
Safety will be assessed in all treated subjects. The rate of treatment-related adverse events leading to drug 
discontinuation within the first 12 weeks of treatment will be assessed.
PFS is defined as the time from treatment assignment in IVRS to the date of the first documented tumor progression 
or death due to any cause, whichever occurs first. 
OS is defined as the time between the date of treatment assignment in IVRS and the date of death due to any cause. 
A subject who has not died will be censored at the last known alive date.
Analysis:
Treatment-related AEs leading to discontinuation will be tabulated using worst grade per NCI CTCAE v 4.0 criteria 
by system organ class and preferred term. All on-study AEs, Grade 3-4 AEs, treatment-related AEs, Grade 3 4 
treatment-related AEs, SAEs, treatment-related SAEs, and AEs leading to discontinuation will be tabulated using 
worst grade per NCI CTCAE v 4.0 criteria by system organ class and preferred term. On-study lab parameters 
including hematology, chemistry, liver function, and renal function and Grade 3-4 Lab Abnormalities will be 
summarized using worst grade NCI CTCAE v 4.0 criteria.
PFS and OS will be summarized descriptively using Kaplan-Meier methodology. Median values of PFS and OS, 
along with two-sided 95% CIs using the Brookmeyer and Crowley method, will be calculated for each cohort. PFS 
rates at 6 and 12 months, and OS rates at 12 and 24 months will also be estimated. Associated two-sided 95% CIs 
will be calculated using the Greenwood formula. Additional survival analysis may be conducted for up to 5 years 
beyond analysis of the primary endpoint.
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6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
6.8 Safety Assessments ........................................................................................... 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 Primary Endpoint Methods ............................................................. 
8.4.2.2 Secondary Endpoint Methods ......................................................... 
 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.5 Biomarker Analyses ................................................................................. 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.7 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
APPENDIX 1 PERFORMANCE STATUS SCALES ................................................. 
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APPENDIX 2 MANAGEMENT ALGORITHMS ....................................................... 
APPENDIX 3 RECIST 1.1 ........................................................................................... 
APPENDIX 4 DEFINITION OF PRIOR RESPONSE TO PLATINUM-BASED 
CHEMOTHERAPY IN SCLC ............................................................................... 
APPENDIX 5 DEFINITION OF PRIOR RESPONSE TO PLATINUM-BASED 
CHEMOTHERAPY IN OVARIAN CANCER ...................................................... 
APPENDIX 6 METHODS OF CONTRACEPTION ................................................... 
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CA209032
nivolumab / ipilimumab
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
subjects with advanced melanoma treated at the dose level of nivolumab 1 mg/kg combined with 
ipilimumab 3 mg/kg had an objective response, the majority of which had deep tumor reduction 
of 80% or more. This deep response compares favorably to results with 3 mg/kg ipilimumab 
monotherapy or nivolumab monotherapy and is the basis for an ongoing randomized 
Phase 3 study in advanced melanoma (CA209067). Studies investigating the efficacy and safety 
of nivolumab in combination with ipilimumab are ongoing in NSCLC and RCC.
The combination of nivolumab and ipilimumab has the potential for increased frequencies of 
adverse events compared to ipilimumab monotherapy or nivolumab monotherapy. The most 
common (reported at > 10% incidence) treatment related AEs are fatigue, rash, pruritus, diarrhea, 
lipase increased, pyrexia, ALT increase, AST increased, amylase increased, and vitiligo. 
This class of AEs are expected for the combination of nivolumab and ipilimumab based on the 
known AE profile of each drug alone. In addition, many of the Grade 3-4 adverse events were 
laboratory in nature (ie, LFTs, lipase, amylase), were without clinical sequalae and have been 
manageable and reversible following intervention dose delays or with systemic steroid treatment. 
However, these AEs have the potential to be fatal if not detected early and managed per the 
established algorithm and fatal AEs have been reported for both ipilimumab and nivolumab 
monotherapy. As of June 2013, one subject died because of a study treatment related adverse 
event (toxic epidermal necrolysis, TEN) in the nivolumab + ipilimumab development program. 
Fatal TEN has previously been reported for ipilimumab monotherapy.
Evaluating nivolumab monotherapy and the combination of nivolumab and ipilimumab in 
subjects with advanced or metastatic solid tumors for which no standard of care in advanced 
lines of treatment exists, will potentially generate efficacy signals as a basis for further clinical 
development in these tumor types.
Across multiple tumors, 3 mg/kg nivolumab as well as 3 mg/kg ipilimumab monotherapy have
demonstrated a tolerable AE profile in hundreds, respectively thousands of subjects that appears 
to be independent of tumor type. The combination of 1 mg/kg nivolumab + 3 mg/kg ipilimumab 
has demonstrated an acceptable AE profile in melanoma and is currently in Phase 3. The same 
regimen is currently being studied in RCC and NSCLC. The following safety measures have 
been employed to ensure safety of the subjects in this current study:

Intense toxicity monitoring will help to ensure the subjects’ safety in Study CA209032, 
including frequent safety conference calls with investigators and representatives of the 
sponsor

A BMS medical safety team (MST) routinely reviews safety signals across the entire 
nivolumab program, including all ongoing combinations with ipilimumab

Two stage design used which will stop an individual arm for lack of sufficient activity

For the combination arm, an initial dose escalating safety evaluation phase will be performed 
to determine the optimal dose for each tumor type independently
In conclusion, the overall risk-benefit assessment for Study CA209032 does justify the conduct 
of the trial.
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BMS-936558 / BMS-734016
nivolumab / ipilimumab
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Council for 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.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment).
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. 
The investigator or BMS should also provide the IRB/IEC with a copy of the Investigator 
Brochure or product labeling information to be provided to subjects and any updates.
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate.
In situations where consent cannot be given to subjects, their legally acceptable representatives 
are clearly and fully informed about the purpose, potential risks, and other critical issues 
regarding clinical studies in which the subject volunteers to participate.
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
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nivolumab / ipilimumab
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 the informed 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 completed for 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 his 
or her informed consent during the study, 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.
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.
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
This is a multicenter Phase 1/2, two stage, open label study of nivolumab monotherapy or 
nivolumab combined with ipilimumab in adult (18 years) subjects with advanced or metastatic 
cancer of one of the following tumor types:
1) Triple Negative Breast Cancer (TNBC)
2) Gastric Cancer (GC)
3) Pancreatic Cancer (PC)
4) Small Cell Lung Cancer (SCLC)
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CA209032
BMS-936558 / BMS-734016
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5) Bladder Cancer (BC)
6) Ovarian Cancer (OC)
Treatment assignment: The assignment to treatment arm and evaluation of safety and activity 
will be performed independently for each tumor type (Figure 3.1-1). For each tumor type, 
subjects will be assigned (described in Section 4.4) to one of the following treatment arms:
Arm N:
Nivolumab monotherapy (3 mg/kg) Q2W
Arm N-I Dose 
 1:
Nivolumab (1 mg/kg) + ipilimumab (1 mg/kg) Q3W for 4 doses, 
then nivolumab (3mg/kg) Q2W
Arm N-I Dose Level 2:
Nivolumab (1 mg/kg) + ipilimumab (3 mg/kg) Q3W for 4 doses, 
then nivolumab (3 mg/kg) Q2W
Arm N-I Dose Level 2b:
Nivolumab (3 mg/kg) + ipilimumab (1 mg/kg) Q3W for 4 doses, 
then nivolumab (3 mg/kg) Q2W
Arm N-I Dose Level 2c:
Nivolumab (3 mg/kg) Q2W + ipilimumab (1 mg/kg) Q6W
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CA209032
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Figure 3.1-1:
Study Design for Each Tumor Type
Notes: N = nivolumab; I = ipilimumab; SCLC = small cell lung cancer; GC = gastric cancer; PC = pancreatic 
cancer; TNBC = triple-negative breast cancer; BC = bladder cancer; OC = ovarian cancer
*dose level 1 (N1 mg/kg Q3W +I1 mg/kg Q2W) and dose level 2 (N1 mg/kg Q3W + I3 mg/kg Q2W); ** dose level 
2b (N3 mg/kg Q3W + I1 mg/kg Q2W); *** dose level 2c (N3 Q2W + I1 Q6W)
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CA209032
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nivolumab / ipilimumab
Dose-escalation Safety Evaluation Phase for Combination Arm: Although the regimen 
currently used in the Phase 3 melanoma study, nivolumab 1 mg/kg IV + ipilimumab 3 mg/kg, 
was expected to also be tolerable in the tumors studied here, an initial dose-escalating safety 
evaluation for the combination arms was conducted with GC, PC, TNBC, or SCLC (described in 
protocol Section 3.1.2). The BC cohort was added to this protocol following the completion of 
the safety evaluations in GC, PC, TNBC, and SCLC at dose level 1 (nivolumab 1 mg/kg, 
ipilimumab 1 mg/kg) which did not reveal safety concerns. Thereby the starting dose level for 
the BC cohort was dose level 2 (nivolumab 1 mg/kg, ipilimumab 3 mg/kg). Six BC patients were 
initially randomized to Dose Level 2, after which enrollment to Dose Level 2b (nivolumab 
3 mg/kg, ipilimumab 1 mg/kg) began.
Enrollment to Stage 1 for Arm N occurred in parallel to the safety evaluation for Arm N-I.
Two Stage Design: GC, PC, TNBC, SCLC Arms will follow a two-stage design to test whether 
nivolumab monotherapy or nivolumab combined with ipilimumab yields an objective response 
rate (ORR) that is of clinical interest in the investigated tumor types. For each tumor type, only 
treatment arms which meet an ORR threshold will proceed from Stage 1 to Stage 2 (described in 
protocol Section 3.1.3). Enrollment to Stage 2 in a given treatment arm can continue even if the 
other treatment arm is still in Stage 1.
For Stage 2, upon completion of enrollment for the initial 40 subjects, additional subjects may be 
assigned into Arm N and Arm N-I up to a total of 100 subjects (including those assigned in 
Stage 1) in each treatment arm of the given tumor type. For tumor types where nivolumab 
monotherapy or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg proceeded to Stage 2, assessment 
of Dose Level 2b in Stage 2 (nivolumab 3 mg/kg + ipilimumab 1 mg/kg, n=up to 70 subjects) 
may be initiated for that tumor type. For SCLC, an additional 250 subjects (second- or third-line) 
will be randomized in a 3:2 ratio to one of the 2 expansion groups: nivolumab 3 mg/kg every 
2 weeks or nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks for 4 cycles followed by 
nivolumab 3 mg/kg.
3.1.1
Modified Designs
Bladder Cancer Cohort
The enrollment for the BC cohorts N and N-I (Dose Level 2b) will be conducted as a One Stage 
Design:

Recently, inhibition of PD-L1 by MPDL3280A was shown to have clinical activity in 
patients with metastatic urothelial bladder cancer, leading to approval of the drug in this 
indication by the FDA.59 In particular, in patients with tumors tested positive for PD-L1 
expression, the overall response rate was 43%. The overall response rate regardless of PD-L1 
expression was 20%.
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CA209032
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nivolumab / ipilimumab

As these data show that checkpoint inhibition has potential to be an active treatment for 
patients with advanced bladder cancer, a Two Stage design with the intent of avoiding to 
expose too many patients to a potentially ineffective treatment does not appear to be 
necessary for this specific tumor type.

Bladder arms N and N-I (Dose Levels 2 and 2b) will be conducted as a One Stage Design 
with the treatment of 26-105 subjects in each arm. The Safety Evaluation Phase for the N-I 
arm will start at Dose Level 2 (nivolumab 1 mg/kg, ipilimumab 3 mg/kg) and will evaluate 
safety and tolerability after the first 6 randomized subjects. Following the N-I safety 
evaluation phase, Dose Levels 2 will enroll 26 subjects and 2b will enroll up to a total of 
105 subjects. Based on the safety evaluations thus far on study, no dose escalation phase is 
necessary for bladder cohort N-I Dose Level 2b (nivolumab 3 mg/kg, ipilimumab 1 mg/kg). 
Ovarian Cancer Cohort
The OC cohorts N-I (Dose Level 2, 2b, 2c) will be conducted as a One Stage Design with the 
enrollment of 40 subjects in each arm. The Dose Level 2c was added to Ovarian Cancer Cohort 
based on the results of CA209003 and CA209012 clinical studies mentioned above. The efficacy 
and tolerability of nivolumab monotherapy observed in CA209003 study with longer follow-up 
of previously treated NSCLC patients suggested a strategy in which nivolumab serves as the 
“base” of a combination regimen, with ipilimumab exposure limited by lower doses and/or less 
frequent administration. This strategy is the basis for new nivolumab and ipilimumab 
combination regimens with nivolumab 3 mg/kg Q2W combined with ipilimumab 1 mg/kg Q6W. 
This regimen was used in CA209012 study with preliminary data showing a promising activity 
and a good safety profile of the combination.
The enrollment to the N-I arm to Dose Levels 2, 2b, and 2c will be conducted simultaneously. 
Due to the low risk of development of new safety signals on the combination arms confirmed by 
the additional information from the combination studies in melanoma, lung, renal cell carcinoma, 
and glioblastoma as well as the clinical study with ipilimumab 10 mg/kg monotherapy in ovarian 
cancer, which did not reveal any new safety signals (
 
 no Safety Evaluation Phase will be employed. Ovarian cancer subjects 
will be followed for related toxicities and decisions to stop treatment will be made on an ongoing 
basis.
3.1.2
Dose-Escalating Safety Evaluation Phase for Arm N-I
The combination of 1 mg/kg nivolumab + 3 mg/kg ipilimumab is already approved for the 
treatment of advanced and metastatic melanoma regardless of BRAF mutational status and has 
more recently been tested in NSCLC and RCC. This regimen is expected to also be tolerable in 
the tumors being studied in this protocol. However, as an added safety precaution, the 
combination of N-I will first be assessed in a dose escalating safety phase. This safety evaluation 
will be conducted for each of the investigated tumor types independently (Table 3.1.2-1).
Recently, data from Phase 1/2 studies in NSCLC and RCC have shown, that the dose level of 1 
mg/kg ipilimumab plus 3 mg/kg nivolumab is well tolerated while potentially preserving the 
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tumor efficacy.9,10 Therefore, a Dose Level 2b (nivolumab 3 mg/kg, ipilimumab 1 mg/kg) will 
be investigated in the Dose-Escalating Safety Evaluation Phase in case Dose Level 2 is not 
tolerable for any of the tumor types being studied.
Table 3.1.2-1:
Dose Cohort for Arm N-I
Dose Cohort Level
Nivolumab (mg/kg)
Ipilimumab (mg/kg)
-1
0.3
1
1
1
1
2
1
3
2b
3
1
The first dose cohort will be Level 1. If this is deemed tolerable, then Level 2 will be initiated. 
If Level 1 is not tolerable, then Level -1 will be initiated. The BC cohort will start at Level 2. 
If Dose Level 2 is not tolerable for a certain tumor type, Dose Level 2b will be investigated. 
There will be no dose escalation beyond Level 2 or Level 2b. Once the highest dose level for 
further investigation has been confirmed in the Dose-Escalating Safety Evaluation Phase, 
Arm N-I will continue enrolling with Stage 1 (Section 3.1.3).
Subjects on active treatment need to be followed up for at least 6 weeks after start of study 
treatment before determination of the tolerability of a dose level. However, tolerability beyond 
6 weeks may also be taken into consideration. The criteria for tolerability (Table 3.1.2-2) are 
based 
on 
drug 
related 
adverse 
events 
leading 
to 
permanent 
discontinuation 
(listed in Section 4.5.5) and include:

If none of the first 3 subjects in a given dose level permanently discontinue treatment due to 
study drug related adverse events within the first 6 weeks, then this dose cohort will be 
deemed as tolerable. For Dose Cohort Level 2 or Dose Cohort Level 2b, at least 6 subjects 
need to have been exposed to this dose level and followed up for at least 6 weeks after start 
of study treatment before the enrollment will proceed in Stage 1. The enrollment of these 
6 subjects will occur in a staggered mode, first 3 subjects will be enrolled and followed up 
for at least 6 weeks before the next 3 subjects will be enrolled and followed up for at least 
6 weeks.

If one or two of the first 3 subjects in a dose cohort permanently discontinue treatment within 
the first 6 weeks due to study drug related adverse events, this cohort will be expanded to 
6 subjects. 

If one of 6 subjects in a dose cohort permanently discontinue treatment due to study drug 
related adverse events within the first 6 weeks, then dose cohort will be deemed as tolerable.

If two of 6 subjects in a dose cohort permanently discontinue treatment within the first 
6 weeks due to study treatment related adverse events, this cohort may be expanded to 
9 subjects. If an expansion is not possible because of the severity of the adverse events 
leading to permanent discontinuation, then this dose cohort will be deemed not tolerable.
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
If no more than two of 9 subjects in a dose cohort permanently discontinue treatment due to 
study treatment related adverse events within the first 6 weeks, then this dose cohort will be 
deemed as tolerable.

If at least three of the first 9 subjects in a dose cohort permanently discontinue treatment 
within the first 6 weeks due to study treatment related adverse events, a Dose -1 Cohort 
(in case of toxicities at Dose Level 1) or a Dose 2b Cohort (in case of toxicities at Dose 
Level 2) may proceed.
For the decision to enroll a Dose -1 or Dose 2b Cohort, the clinical severity of the adverse events 
leading to permanent discontinuation in the previous Dose Cohort will be taken into 
consideration.
Table 3.1.2-2:
Dose Cohort for Arm N-I
Number of subjects treated and 
followed up for at least 6 weeks after 
start of study treatment
Number of subjects with permanent 
discontinuation due to treatment 
related adverse events
Next Step
3
0
Dose tolerable
3
1-2
Expand to 6 subjects
6
1
Dose tolerable
6
2
Expand to 9 subjects
9
2
Dose tolerable
9
3
Dose not tolerablea
a discussion with investigators to review risk/benefit taking into account reversibility of AEs and depth of response
3.1.2.1
Evaluation of Risk/Benefit for Doses that do not meet Tolerable Criteria
In the event of 3 of the first 9 subjects requiring permanent discontinuation, a discussion with 
investigators may be held to review the risk/benefit of this regimen. The rationale for this 
evaluation is that the most frequent severe drug related AEs for the combination in melanoma 
have been asymptomatic, reversible laboratory events (ie, LFTs and lipase) and there is 
preliminary evidence of deep and durable responses in the N-I arm in advanced melanoma 
(CA209004). Therefore, a discussion of the risk/benefit of the regimen will be triggered if the 
following criteria are met:

A majority of subjects who discontinue due to treatment related AEs have deep tumor 
response (ie, > 80% reduction)

All treatment related AEs leading to discontinuation are non-fatal, reversible and without 
severe sequela (ie, GI perforation)

A majority of the treatment related AEs are laboratory in nature, asymptomatic, and 
monitorable via routine blood draws
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If a decision is made to continue with a regimen because of a favorable risk/benefit profile 
(ie, non-fatal AEs in subjects with near CRs that are durable) and despite meeting the ‘not 
tolerable’ criteria above, then IRBs must be notified, ICFs must be updated, and discussion of the 
risk/benefit must be documented with all future subjects who enroll on this regimen.
3.1.3
Staged Enrollment (Stage 1 and Stage 2)
3.1.3.1
Stage 1
This Stage is intended to assess the efficacy in 18 subjects per treatment arm per tumor type to 
determine whether enrollment should continue to Stage 2. For efficacy determination, each Arm 
within each tumor type will be assessed independently.
Arm N: The enrollment and treatment of 18 subjects to Arm N per tumor type can begin while 
the initial Dose Cohort for Arm N-I in this tumor type is still ongoing. The dose level in Arm N 
is 3 mg/kg nivolumab IV every two weeks (Q2W). This dose has been established in more than 
700 subjects with various tumor types exposed to nivolumab monotherapy with a tolerable 
AE profile. Therefore no dose adjustments for Arm N are planned.
Arm N-I: Up to 18 subjects will be enrolled and treated in this arm per tumor type at the highest 
tolerated Dose Level determined during the Dose Escalating Safety Evaluation phase. 
The 3-9 subjects treated at the highest dose level confirmed for further investigation from the 
Dose Escalating Safety Evaluation phase will be counted as part of the 18 required subjects.
3.1.3.2
Criteria to proceed from Stage 1 to Stage 2
The decision to proceed from Stage 1 to Stage 2 will be made for each tumor and for each 
treatment arm independently and include (Table 3.1.3.2-1):

2 or more of 18 subjects in a given arm must have confirmed PR or CR before enrollment for 
that arm will be continued in Stage 2. The tolerability of the regimen will continue to be 
evaluated by the Sponsor with the investigators to ensure that it is acceptable for continued 
enrollment.

Subjects with initial PD per RECIST 1.1 who continue treatment in their initially 
assigned treatment arm beyond progression (Section 4.5.7) and subsequently reach 
confirmed immune related CR or PR (relative to initial tumor assessment) and including 
any new measurable lesions within the sum of all target lesions, will be considered as 
having an objective response for the purposes of meeting criteria for moving from 
Stage 1 to Stage 2. Although not standard RECIST 1.1, these immune related response 
criteria using unidimensional measurements account for the unusual immune related 
tumor response patterns reported for both ipilimumab and nivolumab.

Once the last subject in a given treatment arm has permanently discontinued treatment for 
any reason or has reached the Week 48 Tumor Assessment, and the above criteria are not 
met, then this treatment arm will not proceed to Stage 2. Ongoing subjects will continue to be 
followed up for efficacy and safety.

In case that 2 or more of subjects in a given arm enrolling in Stage 1 have confirmed PR or 
CR, but the enrollment of 18 subjects for Stage 1 has not been completed or 18 subjects have 
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been enrolled but have not been randomized and started treatment at that timepoint, the 
following applies:

Arm N: the enrollment for that arm can be continued in Stage 2. The tolerability of the 
regimen will continue to be evaluated by the Sponsor with the investigators to ensure that 
it is acceptable for continued enrollment.

Arm N-I: at least 9 subjects need to have been exposed to the highest dose level which 
has been confirmed for Stage 1 and followed up for at least 6 weeks after start of study 
treatment before the enrollment for that arm can be continued in Stage 2. The tolerability 
of the regimen will continue to be evaluated by the Sponsor with the investigators to 
ensure that it is acceptable for continued enrollment.
Table 3.1.3.2-1:
Efficacy criteria to proceed from Stage 1 to Stage 2
Efficacy criteria
Next Step
2 or more of 18a subjects in a given arm have confirmed PR or CR
Go into Stage 2
1 or no of 18a subjects in a given arm have confirmed PR or CR.
No Go into Stage 2
a see Section 3.1.3.2 last bullet point for further clarification
3.1.3.3
Stage 2
Arm N: For treatment Arm N of the given tumor type that continues to Stage 2, additional 
subjects will be assigned to a total of 40 subjects, inclusive of those enrolled in Stage 1. For 
tumor types where nivolumab monotherapy proceeded to Stage 2, assessment of Dose Level 2b 
in Stage 2 (nivolumab 3 mg/kg + ipilimumab 1 mg/kg, n=40 subjects) will be initiated for that 
tumor type. A separate evaluation of Dose Level 2b may be necessary if the safety and 
tolerability of Dose Level 2 has not been confirmed.
Arm N-I (Dose Level 2): In case treatment Arm N-I at Dose Level 2 proceeds to Stage 2, 
additional subjects will be assigned to a total of 40 subjects at Dose Level 2, inclusive of those 
enrolled in Stage 1. In order to investigate the Dose Level 2b with a potentially better tolerability 
while preserving tumor efficacy, an additional 40 subjects at Dose Level 2b will be enrolled once 
Arm N-I Dose Level 2 proceeds to Stage 2. In this case, a separate safety evaluation of Dose 
Level 2b is not necessary, as the safety and tolerability of Dose Level 2 had already been 
confirmed previously. 
Within a given tumor type, the treatment arms can proceed to Stage 2 independent of the status 
of the other treatment arm. 
For Stage 2, upon completion of enrollment of the initial 40 subjects, additional subjects may be 
assigned into Arm N and Arm N-I up to a total of 100 subjects (including those assigned in 
Stage 1) in each treatment arm of the given tumor type. For tumor types where nivolumab 
monotherapy or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg proceeded to Stage 2, assessment 
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of Dose Level 2b in Stage 2 (nivolumab 3 mg/kg + ipilimumab 1 mg/kg, n=up to 70 subjects) 
may be initiated for that tumor type.
3.1.3.4
Modified Design Bladder Cancer Cohort 
Bladder arms N and N-I (Dose Levels 2 and 2b) will be conducted as a One Stage Design with 
the treatment of 26-105 subjects in each arm. The Safety Evaluation Phase for the N-I arm will 
start at Dose Level 2 (nivolumab 1 mg/kg, ipilimumab 3 mg/kg) and will evaluate safety and 
tolerability after the first 6 randomized subjects. Following the N-I safety evaluation phase, Dose 
Levels 2 will enroll 26 subjects and 2b will enroll up to a total of 105 subjects. Based on the 
safety evaluations thus far on study, no dose escalation phase is necessary for bladder cohort N-I 
Dose Level 2b (nivolumab 3 mg/kg, ipilimumab 1 mg/kg).
3.1.3.5
Arm N-I (Dose Level 2b)
Based on the safety evaluations thus far on study, no dose escalation phase is necessary for 
bladder cohort N-I Dose Level 2b (nivolumab 3 mg/kg, ipilimumab 1 mg/kg).
3.1.4
SCLC Expansion
SCLC cohorts Arm N and Arm N-I met the pre-specified safety and efficacy criteria and 
proceeded to Stage 2. Based on an interim data review, disease control rates (SD + PR + CR) of 
36% and 57% for Arms N and N-I, respectively, were estimated. In order to further investigate 
nivolumab and nivolumab combined with ipilimumab activity in specific SCLC subpopulations, 
the SCLC expansion cohorts will enroll additional subjects based on response to prior treatment 
and the number of previous therapies. Up to 250 second or third line subjects will be randomized
in a 3:2 ratio to one of 2 expansion groups: Arm A (150 subjects treated with nivolumab 3 mg/kg 
every 2 weeks (Q2W)) or Arm B (100 subjects treated with nivolumab 1 mg/kg + ipilimumab 
3 mg/kg every 3 weeks (Q3W) for 4 cycles followed by nivolumab 3 mg/kg (Q2W) and will be 
stratified for number of prior treatment lines (1 vs 2 prior chemotherapy regimens).
The study population for the SCLC expansion cohort is specified as follows:

Histopathologically or cytologically confirmed diagnosis of SCLC.

All subjects had platinum-based first-line treatment. Subjects with previous second-line 
chemotherapy treatment are eligible as well.

Subjects with platinum refractory, resistant, or sensitive disease are eligible.

Subjects with initial diagnosis of limited or extensive disease are eligible.

Documented objective radiographic disease progression at study entry.
Tumor assessments for subjects in the SCLC expansion cohort will undergo a BICR assessment.
The crossover option refers only to the original cohorts and not the new cohorts enrolled under or 
after Amendment 09.
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3.1.5
Duration of Study Treatment
The study treatment will be continued until disease progression (investigator-assessed 
RECIST 1.1-defined progression) or occurrence of unacceptable toxicity as defined in 
Section 4.5.5. For subjects achieving confirmed CR or a PR for more than 3 months (long lasting 
PR) the investigator may decide to hold treatment for this subject after discussion with the 
medical monitor of the sponsor. During the treatment hold subjects should follow all study 
procedures as specified in Section 5.1. Subjects for which treatment was held following long 
lasting responses and who experience a recurrence of disease progression may reinitiate their last 
study treatment. Before reinitiating treatment, the investigator should discuss the individual case 
with the medical monitor and document in the study records.
3.1.6
Crossover for Subjects in Arm N
Subjects in Arm N may crossover to Arm N-I if all of the following criteria are met:

The Safety Evaluation Phase for the N-I regimen has been completed and at least 6 subjects 
have been exposed to the dose level used for Stage 1 of the N-I regimen. In case 
Dose Level 2b has been activated and completed the safety assessment, subjects for cross 
over will be assigned to Dose Level 2 or Dose Level 2b after discussion between the sponsor 
and investigator taking into consideration previous safety and efficacy signals at these dose 
levels and the status of the individual subject planned for cross over.

Subject has further disease progression (investigator-assessed RECIST 1.1-defined 
progression according to description provided in Section 4.5.7, confirmed at least 4 weeks 
after the initial tumor assessment showing progression (definition of confirmed progression
see Appendix 3)) in the absence of clinical deterioration. For subjects with clear evidence of 
new or progressing brain metastases a confirmation is not required. These subjects may 
proceed with brain radiation therapy and, if necessary, with gamma-knife or surgical 
resection, after having completed the therapy a cross over to Arm N-I can be considered 
(see Section 3.4.2.1).

Subjects with rapidly progressing tumors under nivolumab monotherapy may undergo 
radiation treatment first before initiation of the cross over after discussion between the 
sponsor and investigator.

Subject has not experienced nivolumab related adverse events leading to permanent 
discontinuation as described in Section 4.5.5.

Subject is not continuing to derive any clinical benefit from nivolumab single agent therapy 
as assessed by the investigator which would allow continuation of nivolumab monotherapy 
(see Section 4.5.8).

Subject is not a SCLC patient enrolled based on the Amendment 09 expansion.

The individual case must be discussed with the medical monitor prior to cross over.
Subjects crossing over to Arm N-I will start treatment at Day 1 Week 1 as described for subjects 
originally randomized to Arm N-I. Subjects who crossed over and subsequently have an 
objective response in Arm N-I will not be considered in the decision making for Arm N-I 
proceeding to Stage 2. Subjects in Arm N-I cannot crossover to Arm N.
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3.1.7
Re-exposure with Nivolumab/Ipilimumab for Subjects in Arm N-I
Subjects in Arm N-I may undergo a re-exposure with nivolumab/ipilimumab if they achieved an 
initial objective response (PR or CR) or stable disease of 3 months and had a subsequent 
documented progression. Subjects must fulfill the following criteria:

Subjects have not experienced any related adverse events as described in Section 4.5.5
(discontinuation criteria).

Eligible subjects will receive up to four doses of nivolumab/ipilimumab (based on treatment 
assigned at randomization) during Re-exposure.
Subjects can receive nivolumab 
monotherapy, if ipilimumab caused toxicities leading to its discontinuation (section 4.5.5)

Dosing may be delayed for toxicity (see Section 4.5.2).

Subjects who have permanently discontinued study therapy for any reason and are in the 
follow up phase may not receive any re-exposure dosing.
3.1.8
Review of Safety
The subjects’ safety will be monitored on an ongoing basis as described fully in Section 7. Safety 
conference calls with investigators and representatives of the sponsor will be held approximately 
every other week with additional meetings as necessary. Decisions for the safety evaluation 
phase of Arm N-I and for continuing from Stage 1 to Stage 2 in both treatment arms will be 
made in conjunction with the investigators. In addition, a BMS medical safety team (MST) 
routinely reviews safety signals across the entire nivolumab program including combination 
studies with ipilimumab.
3.1.9
Treatment Beyond Progression
Treatment beyond investigator-assessed RECIST 1.1-defined progression will be permitted if the 
subject experiences investigator-assessed clinical benefit and the subject is tolerating the study 
treatment (Section 4.5.7).
3.1.10
Intrapatient Dose Reductions
Intrapatient dose reduction is not permitted for any reason. Dose delays for the management of 
study treatment related adverse events are described in Section 4.5.2.
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3.1.12
Study Phases
This study will consist of three phases: screening, treatment, and follow-up.
Screening Phase:

Begins by establishing the subject’s initial eligibility and signing of the informed consent 
form (ICF).

Subject is enrolled using the Interactive Voice Response System (IVRS).
Treatment Phase:

Begins with the vial assignment call to the IVRS.

A negative pregnancy test must be documented within 24 hours prior to the start of 
investigational product.

Within 3 days from treatment assignment, the subject must receive the first dose of study 
medication:

Arm N (nivolumab monotherapy):
Nivolumab 3 mg/kg IV every two weeks (Q2W). See Table 4.5-1

Arm N-I (nivolumab + ipilimumab)
Dose Escalation Phase:
Staged Enrollment Phase: Dose Level determined in Dose Escalation Phase. See Table 4.5-2 and 
Table 4.5-3.

Dose Level 1, Nivolumab 1 mg/kg IV combined with ipilimumab 1 mg/kg IV Q3W for 
4 doses, then nivolumab 3 mg/kg IV Q2W. See Table 4.5-2 and Table 4.5-3.

Dose Level 2: Nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV Q3W for 
4 doses, then nivolumab 3 mg/kg IV Q2W.
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
Dose Level 2b: Nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV Q3W for 
4 doses, then nivolumab 3 mg/kg IV Q2W.

Dose Level 2c: Nivolumab 3 mg/kg IV Q2W combined with ipilimumab 1 mg/kg Q6W.

Adverse event assessments will be documented at each visit throughout the study.
On-study laboratory assessments (after D1W1) should be drawn within 72 hours prior to dosing 
according to the schedule in Table 5.1-2, Table 5.1-3, Table 5.1-4, and Table 5.1-5.

Women of child bearing potential (WOCBP) must have a negative pregnancy test 
documented as follows:

Arm N and Arm N-I2c: before every other nivolumab administration, within 24 hours 
prior to dosing.

Arm N-I: before every combined nivolumab / ipilimumab administration, within 24 hours 
prior to dosing. Thereafter every 4 weeks, within 24 hours prior to nivolumab dosing.

PK samples and immunogenicity samples will be collected according to the schedule in
Section 5.5.

Study drug dosing may be delayed for toxicity. See Section 4.5.2.

Treated subjects will be evaluated for response according to the RECIST 1.1 guidelines 
beginning 6 weeks (1 week) after first dose and continuing every 6 weeks (1 week) for 
the first 24 weeks, and then every 12 weeks (1 week) while on treatment or on treatment 
hold for any reason until disease progression (investigator-assessed RECIST 1.1-defined 
progression) or treatment discontinuation, except for subjects treated beyond progression or 
who discontinued treatment for other reasons than PD.
This phase ends when the subject is discontinued from study therapy. For a complete list of 
reasons for treatment discontinuation, see Section 4.5.5.
Follow-Up Phase

Begins when the decision to discontinue a subject from study therapy is made 
(no further treatment with study therapy).
Two follow-up visits include collection of PK/immunogenicity samples Table 5.1-6, Table 5.5.1-
1, and Table 5.5.1-2.

Subjects who discontinue treatment for reasons other than tumor progression will continue to 
have tumor assessments beginning 6 weeks (1week) after first dose and continuing every 
6 weeks (1 week) for the first 24 weeks from first dose, and every 12 weeks (1 week) 
thereafter until disease progression (investigator-assessed RECIST 1.1-defined progression).
This does also apply to subjects whose treatment was put on hold after achieving confirmed 
CR or PR for more than 3 month (long lasting PR).
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
Subjects will be followed for drug-related toxicities until these toxicities resolve, return to 
baseline or are deemed irreversible. All adverse events will be documented for a minimum of 
100 days after last dose.

Follow up visits should be made in-person. If a subject is unable to make an in-person visit, 
the reason should be clearly documented at the site.

Follow-up visit 1 (FU1) = 35 days from the last dose 7 days or coincide with the date of 
discontinuation (7 days) if date of discontinuation is greater than 42 days after last dose, 
Follow-up visit 2 (FU2) = 80 days (7 days) from follow-up visit 1.

After completion of the first two follow-up visits, subjects will be followed every 3 months 
for survival via in-person visits, phone or email. Ad hoc survival data requests may be made 
during the study as well, particularly during database locks.
3.1.13
Total Study Duration
It is projected that the accrual for the Initial Dose Cohort and the Efficacy Signal Detection -
Stage 1 of the study will be completed within 4 months after FPFV and that the results of the 
interim analysis will be available 9 months after FPFV. The final analysis is expected at 
60 months after FPFV.
3.2
Post Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive study drug. Study drug will be provided via an extension of the study, a 
rollover study requiring approval by responsible health authority and ethics committee or 
through another mechanism at the discretion of BMS. BMS reserves the right to terminate access 
to study drug if any of the following occur: a) the marketing application is rejected by 
responsible health authority; b) the study is terminated due to safety concerns; c) the subject can 
obtain medication used in this study as study treatment from a government sponsored or private 
health program; or d) therapeutic alternatives become available in the local market.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed consent 
form in accordance with regulatory and institutional guidelines. This must be obtained 
before the performance of any protocol related procedures that are not part of normal 
subject care
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests, fresh tumor biopsies, and other requirements of the study.
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2. Target Population
a) Subjects with pathologically confirmed locally advanced or metastatic disease of the 
following tumor types:
i)
Women with histologically or cytologically confirmed breast carcinoma who must 
meet all of the following:
(1) Tumor must be “triple receptor negative” defined as ER/PR negative per local lab 
and HER-2 negative defined as HER-2 0 or 1+ by IHC, or IHC 2+ and ISH not 
amplified, or ISH-non amplified.
AND
(2) Subjects must have progression or refractory disease. Subjects must have had at 
least 1 chemotherapy regimen for the treatment of metastatic (Stage IV) or locally 
advanced disease.
OR
(3) Subject actively refuses chemotherapy for the treatment of metastatic (Stage IV) 
or locally advanced disease considered as standard treatment for this disease 
stage, despite being informed by the investigator about the treatment options. 
Subjects actively refusing chemotherapy must have had progression or refractory 
disease prior to starting study treatment. The subject’s refusal must be thoroughly 
documented. The investigator will discuss each individual subject refusing 
chemotherapy with the sponsor’s medical monitor to confirm eligibility.
ii) Subjects with histologically confirmed Gastric or Gastro-Esophageal Junction 
Carcinoma (including adenocarcinoma arising from the lower esophagus) who must 
meet all of the following:
(1) Subjects must have progression or refractory disease. Subjects must have had at 
least 1 chemotherapy regimen for the treatment of metastatic (Stage IV) or locally 
advanced disease. Subjects with HER-2 positive tumors must have had previous 
treatment with trastuzumab.
OR
(2) Subject actively refuses chemotherapy or biological therapy for the treatment of 
metastatic (Stage IV) or locally advanced disease considered as standard 
treatment for this disease stage, despite being informed by the investigator about 
the treatment options. Subjects actively refusing chemotherapy must have had 
progression or refractory disease prior to starting study treatment. The subject’s 
refusal must be thoroughly documented. The investigator will discuss each 
individual subject refusing chemotherapy with the sponsor’s medical monitor to 
confirm eligibility.
iii) Subjects with histologically confirmed Pancreatic adenocarcinoma who must meet all 
of the following:
(1) Subjects must not have clinically relevant ascites at baseline, such as ascites in 
need of paracentesis.
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AND
(2) Subjects must have had best response of stable disease, or progression or 
refractory disease during or after at least 1 chemotherapy regimen for the 
treatment of metastatic (Stage IV) or locally advanced disease
OR
(3) Subject actively refuses chemotherapy for the treatment of metastatic (Stage IV) 
or locally advanced disease considered as standard treatment for this disease 
stage, despite being informed by the investigator about the treatment options. 
Subjects actively refusing chemotherapy must have had best response of stable 
disease, or progression or refractory disease prior to starting study treatment. The 
subject’s refusal must be thoroughly documented. The investigator will discuss 
each individual subject refusing chemotherapy with the sponsor’s medical 
monitor to confirm eligibility.
iv) Subjects with histologically or cytologically confirmed small cell lung cancer. 
Subjects must have progression or refractory disease. Subjects must have had at least 
1 platinum based chemotherapy regimen for the treatment of limited or extensive 
stage disease, but not more than 2 prior chemotherapy regimens. For subjects to be 
enrolled in the SCLC expansion cohorts to following eligibility criteria apply:
(1) All subjects must have had platinum-based first-line treatment. Subjects with 
previous second-line chemotherapy treatment are eligible as well.
(2) Subjects with platinum refractory, resistant, or sensitive disease are eligible 
(Appendix 4).
(3) Subjects with initial diagnosis of limited or extensive disease are eligible.
(4) Documented objective radiographic disease progression at study entry.
v) Subjects with histologically or cytologically confirmed urothelial carcinoma 
(including mixed histologies of urothelial carcinoma with elements of other subtypes) 
of the renal pelvis, ureter, bladder, or urethra, who must meet all of the following:
(1) Subjects must have progression or refractory disease. Subjects must have had at 
least 1 platinum based chemotherapy regimen for the treatment of metastatic 
(Stage IV) or locally advanced unresectable disease.
OR
(2) Subjects with disease recurrence within 1 year of completing a platinum based 
neoadjuvant or adjuvant therapy.
OR
(3) Subject actively refuses chemotherapy for the treatment of metastatic (Stage IV) 
or locally advanced unresectable disease considered as standard treatment for this 
disease stage, despite being informed by the investigator about the treatment 
options. Subjects actively refusing chemotherapy must have had progression or 
refractory disease prior to starting study treatment. The subject’s refusal must be 
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thoroughly documented. The investigator will discuss each individual subject 
refusing chemotherapy with the sponsor’s medical monitor to confirm eligibility.
vi) Subjects with histologically confirmed ovarian carcinoma (including epithelial 
ovarian cancer (OC), primary peritoneal, or fallopian tube carcinoma) who must meet 
all of the following: 
(1) Subjects must have received one platinum-based chemotherapeutic regimen for 
management of primary disease, possibly including intraperitoneal therapy, 
consolidation, biologic/targeted (non-cytotoxic) agents (eg, bevacizumab) or 
extended therapy administered after surgical or non-surgical assessment. Subjects 
are allowed to have received, but are not required to have received subsequent 
cytotoxic regimens for management of recurrent or persistent disease. For the 
purposes of this study, PARP inhibitors given for recurrent or progressive disease 
will be considered cytotoxic. A line of therapy is defined as a regimen used to 
treat initial disease (frontline) or following disease progression (second and 
subsequent lines). A change in regimen for reasons of toxicity or 
consolidation/maintenance in the absence of disease progression does not 
constitute a new line of therapy.
(2) Subjects must have documented disease progression after completion of their 
most recent regimen.
(3) Subjects with platinum refractory, resistant, or sensitive disease are eligible 
(Appendix 5).
b) Subjects must have measurable disease by CT or MRI per RECIST 1.1 criteria 
(see Appendix 3). (Radiographic tumor assessment must be performed within 28 days 
prior to first dose).
c) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
(refer to Appendix 1).
d) Subjects must consent to allow for a baseline tumor biopsy. Baseline tumor biopsies 
should preferably be performed from a tumor site that is NOT the only site of measurable 
disease. For subjects with only one site of measurable disease, tumor biopsies are allowed 
if at least one of the following criteria is met:
-
CT imaging performed after biopsy and there is still measurable disease or
-
The type of biopsy is not expected to impact the measurability (eg, core needle 
biopsy) regardless on when imaging occurred, prior to or after biopsy.
Tumor material from biopsies done before the screening period is acceptable if the biopsy 
was performed within 3 months prior to the planned treatment start and no other systemic 
cancer therapy was administered in the meanwhile.
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e) All baseline laboratory requirements will be assessed and should be obtained within 
14 days of first dose. Screening laboratory values must meet the following criteria:
i)
WBCs 
2000/µL
ii)
Neutrophils 
1500/µL
iii) Platelets 
100 x 10³/µL
iv) Hemoglobin 
9.0 g/dL
v)
Serum creatinine 1.5 x ULN or calculated creatinine clearance (CrCl) 
40 mL/minute (using Cockcroft/Gault formula)
Female CrCl = (140- age in years) x weight in kg x 0.85
                                   72 x serum creatinine in mg/ dL
Male CrCl = (140- age in years) x weight in kg x 1.00
                                      72 x serum creatinine in mg/ dL
vi) AST 
3 x ULN 
vii) ALT 
3 x ULN 
viii) Total Bilirubin
1.5 x ULN (except subjects with Gilbert Syndrome who can have 
total bilirubin < 3.0 mg/dL)
ix) Albumin 3 g/dL
x)
Lipase 1.5 ULN. Subjects with Lipase > 1.5 ULN may enroll if there are neither 
clinical nor radiographic signs of a pancreatitis.
xi) Amylase 1.5 ULN. Subjects with Amylase > 1.5 ULN may enroll if there are 
neither clinical nor radiographic signs of a pancreatitis.
f)
Prior focal radiotherapy to an isolated bony or soft tissue metastasis must be completed at 
least 2 weeks before study drug administration. 
g) Subject Re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been assigned / has 
not been treated). If re-enrolled, the subject must be re-consented and assigned a new 
subject number from IVRS.
3. Age and Reproductive Status
a) Men and women 18 years of age
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
24 hours prior to the start of study drug.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception from the time 
of enrollment for the duration of treatment with study drug (s) plus approximately 5 half-
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lives of study drug (s) plus 30 days (duration of ovulatory cycle) for a total of 5 months
post treatment completion.
e) Men who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug (s) plus 
approximately 5 half-lives of study drug (s) plus 90 days (duration of sperm turnover) for 
a total of 7 months post-treatment completion.
f)
Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However WOCBP must still undergo 
pregnancy testing as described in these sections.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% per year when used consistently and correctly.
At a minimum, subjects must agree to use one highly effective method of contraception. See 
Appendix 6 for details on highly effective methods of contraception.
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are 
eligible if these have been treated and there is no magnetic resonance imaging (MRI) 
evidence of progression for at least 4 weeks after treatment is complete and within 
28 days prior to first dose of study drug administration. There must also be no 
requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day 
prednisone equivalents) for at least 2 weeks prior to study drug administration. Subjects 
with incidental findings of asymptomatic brain metastases at screening may start study 
treatment without prior radiation treatment after discussion between the sponsor and 
investigator.
2. Medical History and Concurrent Diseases
a) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may 
increase the risk associated with study participation or study drug administration, impair 
the ability of the subject to receive protocol therapy, or interfere with the interpretation of 
study results.
b) Other prior malignancy active within the previous 3 years except for local or organ 
confined early stage cancer that has been definitively treated with curative intent, does 
not require ongoing treatment, has no evidence of residual active disease, and has a 
negligible risk of recurrence and is therefore unlikely to interfere with the primary and 
secondary endpoints of the study, including response rate and safety.
c) Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, 
type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only 
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requiring hormone replacement, or conditions not expected to recur in the absence of an 
external trigger are permitted to enroll.
d) Subjects with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 days of first dose. Inhaled or topical steroids, and adrenal replacement steroid doses 
are permitted in the absence of active autoimmune disease.
e) Prior therapy with experimental anti-tumor vaccines; any T cell co-stimulation or 
checkpoint pathways, such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-CTLA-4 antibody, including ipilimumab; or other medicines specifically targeting 
T cell is also prohibited.
f)
All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must 
have resolved to grade 1 (NCI CTCAE version 4) or baseline before administration of 
study drug. Subjects with toxicities attributed to prior anti-cancer therapy which are not 
expected to resolve and result in long lasting sequelae, such as neuropathy after 
platinum-based therapy, are permitted to enroll.
g) Treatment with any chemotherapy, radiation therapy, biologics for cancer, or 
investigational therapy within 28 days of first administration of study treatment (subjects 
with prior cytotoxic or investigational products < 4 weeks prior to treatment might be 
eligible after discussion between investigator and sponsor, if toxicities from the prior 
treatment have been resolved to CTC grade 1 level). 
h) Subjects which have been previously enrolled and randomized in Studies BMS 
CA209331 or BMS CA209451 are not eligible.
3. Physical and Laboratory Test Findings
a) Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBV sAg) test or 
positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV 
antibody test indicating acute or chronic infection.
b) Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be 
performed at sites where mandated locally.
c) Subjects must not be dependent on continuous supplemental oxygen use.
4. Allergies and Adverse Drug Reaction
a) History of allergy to study drug components.
b) History of severe hypersensitivity reaction to any monoclonal antibody.
5. Sex and Reproductive Status
a) WOCBP who are pregnant or breastfeeding.
b) Women with a positive pregnancy test at enrollment or prior to administration of study 
medication.
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 
(eg, infectious disease) illness
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3.5
Discontinuation of Subjects from Treatment
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness

Additional protocol specified reasons for discontinuation (see Section 4.5.5).
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
All subjects who discontinue investigational product should comply with protocol specified 
follow-up procedures as outlined in Section 5. The only exception to this requirement is when a 
subject withdraws consent for all study procedures including post-treatment study follow-up or 
loses the ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment 
of either a psychiatric or physical illness).
If study 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.
For subjects achieving confirmed CR or a PR for more than 3 month (long lasting PR) the 
investigator may decide to hold treatment for this subject after discussion with the medical 
monitor of the sponsor. Subjects for which treatment was held following long lasting responses 
and who experience a recurrence of disease progression may reinitiate their last study treatment. 
Before reinitiating treatment, the investigator should discuss the individual case with the medical 
monitor and document in the study records.
3.6
Post Treatment Study Follow up
In this study, objective response rate is a key endpoint of the study. Tumor responses initiated by 
immunotherapy with nivolumab or nivolumab combined with ipilimumab may evolve after 
treatment discontinuation. Therefore, post treatment study follow-up is of critical importance and 
is essential to preserving subject safety and the integrity of the study. Subjects who discontinue 
study treatment must continue to be followed for collection of outcome and/or survival follow-up 
data as required and in line with Section 5 until death or the conclusion of the study.
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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 
Sponsor-retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, in order to obtain updated contact information. If after all 
attempts, the subject remains lost to follow-up, then the last known alive date as determined by 
the investigator should be reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drugs include both Non-investigational (NIMP) and Investigational Medicinal Products 
(IMP) and can consist of the following:

All products being tested or used as a comparator in a clinical trial. 

Study required premedication, and 

Other drugs administered as part of the study that are critical to claims of efficacy 
(eg, background therapy, rescue medications)

Diagnostic agents: (such as glucose for glucose challenge) given as part of the protocol 
requirements must also be included in the dosing data collection.
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4.1
Investigational Product
Table 4.1-1:
Product Description: Treatment Period
Product Description and 
Dosage Form
Potency
Primary Packaging
(Volume)/ Label Type
Secondary Packaging
(Qty) /Label Type
Appearance
Storage Conditions
(per label)
BMS-936558-01 Solution 
for Injectiona
100 mg 
(10 mg/mL)
10 mL per vial/ 
Open-label
10 vials per carton/
Open-label
Clear to opalescent colorless to 
pale yellow liquid. May contain 
particles
2 to 8°C. Protect from 
light and freezing
Ipilimumab Solution for 
Injection
200 mg 
(5 mg/mL)
40 mL per vial/
Open-label
4 vials per carton/
Open-label
Clear, colorless to pale yellow 
liquid. May contain particles
2 to 8°C. Protect from 
light and freezing
a Nivolumab is labeled as BMS-936558-01 Solution for Injection
Premedications or medications used to treat infusion-related reactions should be sourced by the investigative sites if available and 
permitted by local regulations.
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An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational product(s) is/are: BMS-936558 (nivolumab) and ipilimumab.
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products. 
In this protocol, non-investigational product(s) is/are: Not Applicable 
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Investigational product documentation must be maintained that includes all processes required to 
ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets).
For non-investigational product, if marketed product is utilized, it should be stored in accordance 
with the package insert, summary of product characteristics (SmPC), or similar.
Please refer to the current version of the Investigator Brochure and/or pharmacy reference sheets 
for complete storage, handling, dispensing, and infusion information for BMS-936558 
(nivolumab) and ipilimumab.
4.3.1
BMS-936558 (Nivolumab)
BMS-936558 (nivolumab) vials must be stored at a temperature of 2°C to 8°C and should be 
protected from light, freezing and shaking. 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.
For details on prepared drug storage and use time of nivolumab under room temperature/light 
and refrigeration, please refer to the BMS-936558 (nivolumab) Investigator Brochure 
sections 3.2.2 and 3.2.3 and/or pharmacy reference sheets.
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Nivolumab injection is to be administered as a 60-minute IV infusion. During drug product 
preparation and handling, vigorous mixing or shaking is to be avoided. Care must be taken to 
assure sterility of the prepared solution as the product does not contain any antimicrobial 
preservative or bacteriostatic agent. Please refer to the nivolumab IB and/or pharmacy reference 
sheets for further details regarding preparation/administration.
4.3.2
Ipilimumab
Ipilimumab injection can be used for IV administration without dilution after transferring to a 
PVC (polyvinyl chloride), non-PVC/non-DEHP (di-(2-ethylhexyl)phthalate) or glass containers 
and is stable for 24 hours at 2-8ºC or room temperature/room light (RT/RL). For additional 
ipilimumab storage instructions, please refer to the ipilimumab IB and/or pharmacy reference 
sheets.
Recommended safety measures for preparation and handling include protective clothing, gloves, 
and safety cabinets.
Ipilimumab is to be administered as a 90-minute IV infusion. 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 and/or pharmacy 
reference sheets for further details regarding preparation/administration.
4.3.3
Nivolumab and Ipilimumab Combination
When both BMS-936558 (nivolumab) and ipilimumab 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.
4.4
Method of Assigning Subject Identification
The subject number will be assigned through an interactive voice response system (IVRS) once 
the subject has signed the informed consent form and is registered. Every subject that signs the 
informed consent form must be assigned a subject number in IVRS. Specific instructions for 
using IVRS will be provided to the investigational site in a separate document.
The investigator or designee will register the subject for enrollment by following the enrollment 
procedures established by BMS. The following information is required for enrollment:

Date that informed consent was obtained

Date of birth

Gender at birth
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Once enrolled in IVRS, enrolled subjects that have met all eligibility criteria will be ready for 
treatment assignment and drug vial assignment through the IVRS. The following information is 
required for drug vial assignment and randomization:

Subject number

Date of birth

Tumor Type

Date tumor tissue sample was shipped to central lab
Subjects meeting all eligibility criteria will be assigned to Arm N (nivolumab), Arm N-I 
(nivolumab 
+ 
ipilimumab) 
or 
Arm 
N-I 
Dose 
level 
2b
(nivolumab 3 mg/kg 
+ 
ipilimumab 1 mg/kg),
Arm N-I Dose level 2c (nivolumab 3 mg/kg every 2 weeks + 
ipilimumab 1 mg/kg every 6 weeks) according to their tumor type and treatment arm availability:

Within a given tumor type, subjects will be assigned to a treatment arm (N or N-I Dose 
Level 2 or N-I Dose Level 2b) in a 1:1:1 ratio guided by randomization schedule if all arms 
are open.

The computer-generated randomization schemas will be prepared by a Randomization 
Coordinator within the Drug Supply Management Department of BMS Research and 
Development.

If only one or two treatment arms are open for enrollment (ie., when enrollment in Arm N-I 
is paused for an interim safety assessment, or when either arm is paused for decision making 
to proceed from Stage 1 to Stage 2 in the Efficacy Signal Detection part), then all newly to be 
assigned subjects will go into the remaining open arm(s).

Once the subject has a treatment assignment, study treatment should be initiated within 
3 working days.

Specific instructions (including an enrollment worksheet) for central enrollment and 
treatment assignment procedure will be provided to the site.
Subjects to be enrolled in the SCLC expansion cohort will be randomized in a 3:2 ratio to one of 
2 expansion groups: Arm A (150 subjects, nivolumab 3 mg/kg every 2 weeks (Q2W) or Arm B 
(100 subjects, nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks (Q3W) for 4 cycles 
followed by nivolumab 3 mg/kg Q2W) and will be stratified for number of prior treatment lines 
(1 vs 2 prior chemotherapy regimens).
Subjects to be enrolled in the OC expansion cohort will be randomized in a 1:1:1 ratio to one of 
3 dose level groups:

Arm A (40 subjects, nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks (Q3W) for 
4 cycles followed by nivolumab 3 mg/kg Q2W)

Arm B (40 subjects, nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks (Q3W) for 
4 cycles followed by nivolumab 3 mg/kg Q2W)

Arm C (40 subjects, Nivolumab (3 mg/kg) Q2W + ipilimumab (1 mg/kg) Q6W)
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4.5
Selection and Timing of Dose for Each Subject
The dosing regimen and schedule for Arm N, Arm N-I Dose Level -1, Dose Level 1, Dose 
Level 2, Dose Level 2b, and Dose Level 2c are detailed in Table 4.5-1 (Arm N), Table 4.5-2
(N-I Arms -1, 1, 2, and 2b, Week 1-12), Table 4.5-3 (N-I Arms -1, 1, 2, and 2b, Week 13 and 
following), and Table 4.5-4 (N-I Arm 2c).
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Table 4.5-1:
Dosing Schedule for Arm N - Nivolumab (BMS-936558) Monotherapy
Every 2 Week Dosing
Day 1, Week 1
Day 1, Week 3
Day 1, Week 5, 7, 9, 
and every other week thereafter
3 mg/kg Nivolumab 
3 mg/kg Nivolumab 
3 mg/kg Nivolumab 
Table 4.5-2:
Dosing Schedule for N-I Arms -1, 1, 2, and 2b (Week 1-12) - Nivolumab (BMS-936558) + Ipilimumab 
Combination
Every 3 Week Dosing
Study Part
Day 1
Week 1
Day 1
Week 4
Day 1
Week 7
Day 1
Week 10
Dose Escalation Phase 
Dose Level -1
0.3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
0.3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
0.3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
0.3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
Dose Escalation Phase 
Dose Level 1
1 mg/kg Nivolumab 
1 mg/kg Ipilimumab
1 mg/kg Nivolumab 
1 mg/kg Ipilimumab
1 mg/kg Nivolumab 
1 mg/kg Ipilimumab
1 mg/kg Nivolumab 
1 mg/kg Ipilimumab
Dose Escalation Phase 
Dose Level 2
1 mg/kg Nivolumab 
3 mg/kg Ipilimumab
1 mg/kg Nivolumab 
3 mg/kg Ipilimumab
1 mg/kg Nivolumab 
3 mg/kg Ipilimumab
1 mg/kg Nivolumab 
3 mg/kg Ipilimumab
Efficacy, Staged Phasea
Dose Level 2
1 mg/kg Nivolumab 
3 mg/kg Ipilimumab
1 mg/kg Nivolumab 
3 mg/kg Ipilimumab
1 mg/kg Nivolumab 
3 mg/kg Ipilimumab
1 mg/kg Nivolumab 
3 mg/kg Ipilimumab
Dose Level 2b
3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
a The staged phase uses maximum tolerable dose identified in escalation phase since it might be different for each tumor type
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Table 4.5-3:
Dosing Schedule for N-I Arms -1, 1, 2, and 2b (Week 13 and following) - Nivolumab (BMS-936558) + 
Ipilimumab Combination
Every 2 Week Dosing
Day 1
Week 13
Day 1
Week 15
Day 1, Week 17, 19, 21 
and every other week thereafter
3 mg/kg Nivolumab 
3 mg/kg Nivolumab 
3 mg/kg Nivolumab 
Table 4.5-4:
Dosing Schedule for N-I Arm Dose Level 2c - Nivolumab (BMS-936558) + Ipilimumab Combination
Every 2 or 6 Week Dosing
Day 1
Week 1
Day 1, Week 3, 5, 7, 9 
and every other week thereafter
Day 1 Week 7, 13, 19 and every 6 weeks 
thereafter
3 mg/kg Nivolumab 
3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
1 mg/kg Ipilimumab
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nivolumab / ipilimumab
Nivolumab and Ipilimumab combination:
When study drugs (nivolumab or ipilimumab) 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 second infusion will always be ipilimumab, and will start no sooner than 30 minutes after 
completion of the nivolumab infusion.
Dosing calculation based on weight:
The dosing calculations should be based on the body weight. If the subject’s weight on the day of 
dosing differs by > 10% from the weight used to calculate the dose, the dose must be 
recalculated. All doses should be rounded to the nearest milligram.
Dosing modifications:
There will be no dose modifications allowed for the management of toxicities of individual 
subjects.
Dosing window Arm N-I Dose Levels 2 and 2b (Week 1-12): subjects may be dosed no less than 
19 days between doses and no more than 3 days from scheduled dose. If dosing is delayed, both 
nivolumab and ipilimumab must be delayed together. If dosing is resumed after a delay, both 
nivolumab and ipilimumab must be resumed on the same day.
Dosing window Arm N and Arm N-I Dose Levels 2 and 2b (Week 13 and following): subjects 
may be dosed no less than 12 days between doses and no more than 3 days from scheduled dose.
Dosing window Arm N-I Dose Levels 2c: subjects may be dosed no less than 12 days between 
doses and no more than 3 days from scheduled dose. If dosing is delayed, both nivolumab and 
ipilimumab must be delayed together.
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF.
4.5.1
Antiemetic Premedications
Antiemetic medications should not be routinely administered prior to dosing of drugs. 
See Section 4.5.6 for subsequent premedication recommendations following a nivolumab- or 
ipilimumab-related infusion reaction.
4.5.2
Dose Delay Criteria
These dose delay criteria apply for all drug-related adverse events attributed to nivolumab, 
ipilimumab, or both. All study drugs must be delayed until treatment can resume 
(see Section 4.5.4).
Nivolumab and ipilimumab administration should be delayed for the following:

Any Grade 2 non-skin, drug-related adverse event, with the following exceptions:

Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment delay
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
Any Grade 3 skin drug-related adverse event

Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
asymptomatic amylase or lipase, lymphocytopenia, AST, ALT, or total bilirubin:
Grade 3 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations, or radiographic signs of pancreatitis do not require a dose 
delay. It is recommended to consult with the BMS Medical Monitor for Grade 3 
amylase or lipase abnormalities.
If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, 
delay dosing for drug-related Grade 2 toxicity
If a subject has baseline grade 1 AST, ALT, or total bilirubin elevation, delay dosing 
for drug-related Grade 3 toxicity
Grade 3 lymphocytopenia not associated with symptoms or clinical manifestations. 
It is recommended to consult with the BMS Medical Monitor for Grade 3 
lymphocytopenia before treatment continuation.

Any adverse event, laboratory abnormality, or concurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
Because of the potential for nivolumab- or ipilimumab-related AEs requiring early recognition 
and prompt intervention, management algorithms have been developed for suspected pulmonary 
toxicity, GI toxicity, hepatotoxicity, endocrinopathy, skin toxicity, neurological toxicity, and 
nephrotoxicity.
In order to standardize the management of adverse events for all subjects, treatment management 
algorithms recommended for utilization in Study CA209032 are included in Appendix 2. 
Adverse event treatment management algorithms included
in the Nivolumab IB or 
Ipilimumab IB might be considered for individual cases.
4.5.3
Dose Modifications
Intrapatient dose reductions for the management of toxicities of individual subjects or dose 
escalations are not permitted.
4.5.4
Criteria to Resume Treatment
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to 
Grade 1 or baseline value, with the following exceptions:

Subjects may resume treatment in the presence of Grade 2 fatigue.

Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for 
reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in the 
presence of Grade 2 AST/ALT OR total bilirubin. Subjects with combined 
Grade 2 AST/ALT AND
total bilirubin values meeting discontinuation parameters 
(Section 4.5.5) should have treatment permanently discontinued.
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
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed.

Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement or glucose controlling agents may resume treatment.
If the criteria to resume treatment are met, the subject should restart treatment at the next 
scheduled timepoint per protocol. However, if the treatment is delayed past the scheduled 
timepoint per protocol, the scheduled study treatment administration will be delayed, but not 
skipped, until dosing resumes. In particular, this is to ensure that subjects in Arm N-I will 
receive 4 administrations of combined nivolumab and ipilimumab treatment if toxicity allows.
If dose delay is necessary for subjects in Arm N-I during Week 1-12, both nivolumab and 
ipilimumab must be delayed until treatment can resume. However, if a nivolumab-related 
infusion reaction prevents subsequent infusion of ipilimumab on the same day, the dose of 
ipilimumab should be replaced as soon as possible. In such instances, at least 19 days must 
elapse between the replacement dose of ipilimumab and the administration of the next dose of 
nivolumab combined with ipilimumab.
If treatment is delayed > 6 weeks from the last dose, the subject must be permanently 
discontinued from study therapy, except as specified in Section 4.5.5.
4.5.5
Discontinuation Criteria
Discontinuation criteria apply for all drug-related adverse events attributed to nivolumab, 
ipilimumab, or both.
Treatment should be permanently discontinued for the following:

Any Grade 2 drug-related uveitis, eye pain, or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment.

Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for drug-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, 
diarrhea, colitis, neurologic toxicity, hypersensitivity reactions, and infusion reactions:

Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic 
toxicity, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation

For Grade 3 endocrinopathy adverse events such as adrenal insufficiency, 
ACTH deficiency, hyper- or hypothyroidosis, or glucose intolerance, which resolve or are 
adequately controlled with physiologic hormone replacement (steroids, thyroid 
hormones) or glucose controlling agents, respectively, do not require treatment 
discontinuation

Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except: 
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
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Any drug-related liver function test (LFT) abnormality that meets the following 
criteria require discontinuation: 

AST or ALT > 8 x ULN

Total bilirubin > 5 x ULN

Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN

Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events which do not require discontinuation:

Grade 4 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations, or radiographic signs of pancreatitis. Consult with the BMS Medical 
Monitor for Grade 4 amylase or lipase abnormalities.

Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset.

For Grade 4 endocrinopathy adverse events such as adrenal insufficiency, 
ACTH deficiency, hyper- or hypothyroidosis, or glucose intolerance, which resolve or are 
adequately controlled with physiologic hormone replacement (steroids, thyroid 
hormones) or glucose controlling agents, respectively, retreatment can be considered after 
discussion with the BMS Medical Monitor.

Grade 4 lymphocytopenia not associated with symptoms or clinical manifestations. It is 
recommended to consult with the BMS Medical Monitor for Grade 4 lymphocytopenia 
before treatment continuation.

Any dosing interruption lasting > 6 weeks with the following exceptions:

Dosing interruptions to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed. Prior to re-initiating treatment in a subject with a dosing interruption 
lasting > 6 weeks, the BMS medical monitor must be consulted. Tumor assessments 
should continue as per protocol even if dosing is interrupted. 

Dosing interruptions > 6 weeks that occur for non-drug-related reasons may be allowed if 
approved by the BMS medical monitor. Prior to re-initiating treatment in a subject with a 
dosing interruption lasting > 6 weeks, the BMS medical monitor must be consulted. 
Tumor assessments should continue as per protocol even if dosing is interrupted.

Any adverse event, laboratory abnormality, or concurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued nivolumab 
or ipilimumab dosing.
If a subject in Arm N-I meets criteria for discontinuation of nivolumab, the subject should 
discontinue both nivolumab and ipilimumab and be taken off the treatment phase of the study 
entirely. However, if the investigator assesses the drug-related AE to be related to ipilimumab 
only and not related to nivolumab, ipilimumab dosing alone may be discontinued while 
nivolumab dosing is delayed until the subject meets criteria to resume nivolumab treatment 
(specified in Section 4.5.4). Nivolumab would be continued at 3 mg/kg with an every 2 week 
dosing interval. The relationship to ipilimumab should be well documented in the source 
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documents and the BMS medical monitor needs to be contacted prior to continuation with 
nivolumab therapy.
4.5.6
Treatment of Nivolumab- or Ipilimumab-Related Infusion Reactions
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, each 
is unlikely to be immunogenic and induce an infusion or hypersensitivity reaction. However, if 
such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritis, 
arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion 
reactions should be reported within 24 hours to the BMS Medical Monitor and reported as an 
SAE if criteria are met. Infusion reactions should be graded according to NCI CTCAE 
(version 4.0) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate: 
For Grade 1 symptoms (Mild reaction; infusion interruption not indicated; intervention not 
indicated):
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes before 
additional nivolumab or ipilimumab administrations.
For Grade 2 symptoms (Moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for 
24 hours):
Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the infusion 
is interrupted, restart the infusion at 50% of the original infusion rate when symptoms resolve; if 
no further complications ensue after 30 minutes, the rate may be increased to 100% of the 
original infusion rate. Monitor subject closely. If symptoms recur then no further nivolumab or 
ipilimumab will be administered at that visit. Administer diphenhydramine 50 mg IV, and 
remain at bedside and monitor the subject until resolution of symptoms. The amount of study 
drug infused must be recorded on the electronic case report form (eCRF). The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) should be administered at 
least 30 minutes before additional nivolumab or ipilimumab administrations. If necessary, 
corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may be 
used.
For Grade 3 or Grade 4 symptoms (Severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
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symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[eg, renal impairment, pulmonary infiltrates]; Grade 4: (life threatening; pressor or ventilatory 
support indicated):
Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV infusion of normal 
saline, and treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of 
a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected 
slowly 
for 
IV 
administration, 
and/or 
diphenhydramine 
50 mg 
IV 
with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored until the 
investigator is comfortable that the symptoms will not recur. Nivolumab or ipilimumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor subject until recovery from symptoms. 
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritis within 1 week after treatment), symptomatic treatment may be given 
(eg, oral antihistamine, or corticosteroids).
4.5.7
Treatment Beyond Disease Progression
As described in Section 1.1.9 accumulating evidence indicates that subjects treated with 
immunotherapy may derive clinical benefit despite evidence of PD77.
Subjects will be permitted to continue with treatment beyond initial RECIST 1.1 defined PD as 
long as they meet the following criteria:

Investigator-assessed clinical benefit
and

Subject is tolerating study drug.
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. The following 
criteria need to be taken into consideration:

Absence of clinical symptoms and signs (including worsening of laboratory values) 
indicating disease progression.

No decline in ECOG performance status.

Absence of rapid progression of disease or of progressive tumor at critical anatomical sites 
(eg, cord compression) requiring urgent alternative medical intervention.
All decisions to continue treatment beyond progression must be discussed with the BMS Medical 
Monitor and documented in the study records.
Subjects must be re-consented in order to continue treatment.
Subjects should discontinue study therapy upon evidence of further progression, defined as an 
additional 10% or greater increase in tumor burden from time of initial progression (including all 
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target lesions and new measurable lesions). Progression in non-target lesions should only be 
unequivocal as defined and described in Appendix 3 compared to initial progression.
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 
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. Subjects who have tumor shrinkage following RECIST-defined progression (ie, immune 
related response; Section 5.4.4 will be also descriptively summarized separately since these 
immune responses may be used in determining Go to Stage 2.
4.5.8
Crossover to Arm N-I
Subjects in Arm N may crossover to Arm N-I if all of the criteria defined in Section 3.1.6 are 
met. Subjects from the SCLC expansion cohort enrolled under or after Amendment 09 are 
excluded from the crossover option. In case Dose Level 2b has been activated and completed the 
safety assessment, subjects for cross over will be assigned to Dose Level 2 or Dose Level 2b
after discussion between the sponsor and investigator taking into consideration previous safety 
and efficacy signals at these dose levels and the status of the individual subject planned for cross 
over.
Before crossover, the investigator should discuss the individual case with the medical monitor 
and document in the study records. 
Subjects must be re-consented prior to crossing over to Arm N-I.
Subjects crossing over to Arm N-I will start treatment at Day 1 Week 1 as described for subjects 
originally randomized to Arm N-I. Subjects who crossed over and subsequently have an 
objective response in Arm N-I, will not be considered in respect to the decision making for 
Arm N-I of proceeding to Stage 2. Subjects in Arm N-I cannot crossover to Arm N.
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 15 mm). 
For statistical analyses that include the investigator-assessed progression date, subjects who 
crossover after 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 in 
Arm N. The tumor assessment confirming PD in Arm N will serve as the baseline for tumor 
assessments in Arm N-I.
4.6
Blinding/Unblinding
Not applicable.
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4.7
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF.
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials, and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible 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 disposal 
vendor must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible 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 provided that appropriate records of disposal are 
kept.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible 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 provided that appropriate records of disposal are 
kept.
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BMS-936558 / BMS-734016
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4.10
Retained Samples for Bioavailability / Bioequivalence
Not applicable.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (CA209032)
Procedure
Screening
Visit
Notes
Eligibility Assessments
Informed Consent
X
May be performed more than 28 days prior to the first dose (must be completed prior to any study related 
procedures) 
Original IC in screening for protocol participation; 
Study allows for re-enrollment of a subject that has discontinued the study as a pre-treatment failure. If re-
enrolled, the subject must be re-consented and assigned a new subject number from IVRS.
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed prior to first dose.
Demographics and Medical 
History
X
For SCLC and Ovarian cancer subjects, evaluation of Platinum-free interval (PFI) from the completion of 
any platinum-based chemotherapy and subsequent disease progression, and Treatment-free-interval (TFI) 
from the completion of any other cytotoxic or targeted based prior treatment line and subsequent disease 
progression will be collected. For Ovarian Cancer, information about BRCA and Homologous Recombinant 
Deficiency (HRD), if available, will be collected
Tumor Tissue Samples
X
Sufficient tumor tissue obtained before start of study treatment in the metastatic setting or from an 
unresectable site (block or minimum of 10 slides for bladder and SCLC subjects and a minimum of 15 
slides for ovarian subjects (if medically justified), obtained from core biopsy, punch biopsy, excisional 
biopsy or surgical specimen). Tumor tissue samples must be shipped from site to central laboratory prior to 
randomization.
Screening/Baseline Tumor 
Assessment
X
CT chest, CT or MRI brain, abdomen, pelvis and all known sites of disease within 28 days prior to first 
dose. For patients with known brain metastasis, an MRI brain is required at baseline. A CT brain is not 
allowed for patients with a history or evidence of known brain metastasis at baseline.
Safety Assessments
Physical Examination
X
Within 14 days prior to first dose
Vital Signs and oxygen 
saturation
X
Including BP, HR, temperature, and oxygen saturation by pulse oximetry (at rest). Obtain vital signs at the 
screening visit and within 72 hours prior to first dose. 
Physical Measurements 
(including performance status)
X
Height, Weight and ECOG status. Within 14 days prior to first dose
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Table 5.1-3:
On-Study Assessments for N-I Arms (Dose Levels 2 and 2b) Week 1-12, Nivolumab + Ipilimumab 
Combination (CA209032)
Procedure
Week 1-12, nivolumab and ipilimumab are 
administered every 3 weeks for 4 doses.
Notes
Day 1, Week 1, 4, 7, 10
Safety Assessments
Targeted Physical Examination
X
Within 72 hours prior to dosing. During treatment hold to be conducted 
every 12 weeks to adjust to the tumor assessment schedule (see Section 
3.1.5).
Vital Signs and Oxygen 
Saturation
X
Including BP, HR, temperature, and oxygen saturation by pulse oximetry. 
Pulse oximetry at rest within 72 hours prior to dosing. During treatment 
hold to be conducted every 12 weeks to adjust to the tumor assessment 
schedule (see Section 3.1.5).
Physical Measurements 
(including performance status)
X
Weight and ECOG status
The dosing calculations should be based on the body weight. If the 
subject’s weight on the day of dosing differs by > 10% from the weight 
used to calculate the dose, the dose must be recalculated. All doses should 
be rounded to the nearest milligram.
During treatment hold to be conducted every 12 weeks to adjust to the 
tumor assessment schedule (see Section 3.1.5).
Adverse Events Assessment
Continuously
eSAEs should be approved in TAO within 5 days from entry
Review of Concomitant 
Medications
Continuously
Note: Immunosuppressive agents are recorded on a separate log page
Laboratory Tests
X
Within 72 hours prior to re-dosing to include CBC w/ differential, LFTs, 
BUN or serum urea level, creatinine, albumin, Ca, Mg, Na, K, Cl, LDH, 
glucose, amylase, lipase, TSH (if TSH result abnormal, subsequent testing 
of Free T4 and Free T3 required).
During treatment hold to be conducted every 12 weeks to adjust to the 
tumor assessment schedule (see Section 3.1.5).
Pregnancy Test (WOCBP only)
X
Serum or urine within 24 hours prior to first dose and then every 3 weeks 
at Week 1-12, then every 4 weeks. During treatment hold to be conducted 
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Table 5.1-3:
On-Study Assessments for N-I Arms (Dose Levels 2 and 2b) Week 1-12, Nivolumab + Ipilimumab 
Combination (CA209032)
Procedure
Week 1-12, nivolumab and ipilimumab are 
administered every 3 weeks for 4 doses.
Notes
Day 1, Week 1, 4, 7, 10
Whole Blood Sample (DNA)
See Section 5.6.8.6 for details regarding 
specific sample timing
Pharmacogenetic research
Optional (refer to Amendment 01 and 07)
Efficacy Assessment
Tumor Assessment
See Notes
Tumor assessments should occur every 6 weeks (1 wk) from first dose 
for the first 24 weeks, then every 12 wks (1 wk) while on treatment or 
on treatment hold due to any reason until disease progression and 
treatment discontinuation, whichever occurs later. Additionally, with the 
exception of crossover participants, tumor assessments will not be 
required upon initiation of subsequent anti-cancer therapy.. 
CT chest, CT or MRI abdomen, pelvis and all known sites of disease. 
Use same imaging method as was used at screening/baseline.
Subjects with a history of brain metastasis should have surveillance 
MRI approximately every 12 weeks, or sooner if clinically indicated
Clinical Drug Supplies
IVRS Drug Vial Assignment
X
Administer Study Treatment
X
See Section 4.5, Note: Within 3 days from vial allocation, the subject must 
receive the first dose of study medication. Subjects may be dosed no less 
than 19 days between doses and no more than 3 days from the scheduled 
dose.
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Table 5.1-5:
On-Study Assessments for N-I Arms (Dose Level 2c) Nivolumab + Ipilimumab Combination 
(CA209032)
Procedure
For Arm N-I Dose level 2c, Nivolumab is 
administered every 2 weeks, Ipilimumab 
is administered every 6 weeks
Notes
Day 1
Week 1, 3, 5, 7, 9, etc
Clinical Drug Supplies
IVRS Drug Vial Assignment
X
Administer Study Treatment
X
See Section 4.5, Note: Within 3 days from vial allocation, the subject must 
receive the first dose of study medication. Subjects may be dosed no less than 
12 days between doses and no more than 3 days from the scheduled dose.
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Table 5.1-6:
Follow-up Assessments (CA209032) - All Subjects
Procedure
Follow Up,a
Visits 1 and 2
Survival,b
Follow up Visits
Notes
Outcomes Research Assessments
QoL
X
X
Collect EQ-5D prior to study drug administration through Week 13, then at 
the same time of subsequent tumor assessments, during Follow Up 1 and 2 
and survival visits. The EQ-5D can be done via a phone contact when a 
clinic visit is not feasible (ie, follow up scans are being done at another 
facility or department) in order to not miss the assessment.
Pharmacokinetic Samples
PK Samples
X
See Section 5.5.1 for schedule of assessments
a Follow-up visit 1 (FU1) = 35 days from the last dose 7 days or coincide with the date of discontinuation (7 days) if date of discontinuation is greater than 
42 days after last dose, Follow-up visit 2 (FU2) = 80 days (7 days) from follow-up visit 1
b Survival visits = every 3 months from FU2 (±14 days) from FU2.
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5.1.1
Retesting During Screening or Lead-in Period
Laboratory parameters and/or assessments that are included in Table 5.1-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified subjects. Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
5.2
Study Materials

NCI CTCAE version 4.0

BMS-936558 (nivolumab) Investigator Brochure

Ipilimumab Investigator Brochure

Laboratory manuals for collection and handling of blood 
 
) and tissue specimens

Site manual for operation of interactive voice response system, including enrollment 
worksheets

Site manual for imaging process and requirements

Manual for entry of local laboratory data

Serious Adverse Events (or eSAE) case report form pages

Pregnancy surveillance forms

RECIST 1.1 pocket guide
5.3
Safety Assessments
At baseline, a medical history will be obtained to capture relevant underlying conditions. The 
baseline examinations should include signs and symptoms, weight, height, ECOG Performance 
Status, BP, HR, temperature, and oxygen saturation by pulse oximetry at rest should be 
performed within 14 days prior to first dose except where noted in Table 5.1-1. 
 
 
Baseline local laboratory assessments should be done within 14 days prior to the first dose and 
include: CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or 
serum urea level, creatinine, albumin, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, lipase, TSH, 
Free T4, Free T3, and Hep B and C testing (HBV sAg and HCV RNA or Ab) (see Table 5.1-1). 
Pregnancy testing for WOCBP (done locally) must be performed within 24 hours prior to the 
initial administration of study drug at baseline and then every 3 weeks for subjects in Arm N-I at 
Week 1-12, then every 4 weeks, and at the safety follow up visits. For subjects in Arm N and N-I 
2c pregnancy testing for WOCBP (done locally) must be performed within 24 hours prior to the 
initial administration of study drug at baseline and then every 4 weeks, and at each safety follow 
up visit.
During treatment hold, pregnancy testing must be performed every 12 weeks and resumed per 
protocol testing once treatment resumes.
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Subjects will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be performed continuously during the treatment phase. During the safety follow-up phase 
(Table 5.1-4) toxicity assessments should be done in person. Once subjects reach the survival 
follow-up phase, either in-person visits or documented telephone calls to assess the subject’s 
status are acceptable.
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.0.
On-study weight, ECOG performance status, and vital signs should be assessed at each on-study 
visit prior to nivolumab dosing. Vital signs should also be taken as per institutional standard of 
care prior to, during and after dosing. Oxygen saturation by pulse oximetry at rest should be 
assessed at each on study visit prior to nivolumab dosing. The start and stop time of the 
nivolumab and the ipilimumab infusion should be documented. Physical examinations are to be 
performed as clinically indicated. If there are any new or worsening clinically significant 
changes since the last exam, report changes on the appropriate non-serious or serious adverse 
event page.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
inducted 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.
Oxygen saturation by pulse oximetry should be obtained prior to each dose of nivolumab or 
ipilimumab and at any time a subject has any new or worsening respiratory symptoms. A reading 
at rest should be obtained at each time point. If a subject shows changes on pulse oximetry or 
other pulmonary-related signs (eg, hypoxia, fever) or symptoms (eg, dyspnea, cough) consistent 
with possible pulmonary adverse events, the patient subject should be immediately evaluated to 
rule out pulmonary toxicity. An algorithm for the management of suspected pulmonary toxicity 
can be found in Appendix 2.
Some of the previously referred to assessments may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
5.3.1
Imaging Assessment for the Study
Images will be submitted to an imaging core lab for central review. Sites will be trained prior to 
scanning the first study subject. Image acquisition guidelines and submission process will be 
outlined in the CA209032 Imaging Manual to be provided by the core lab. Any incidental 
findings of potential clinical relevance that are not directly associated with the objectives of the 
protocol should be evaluated and handled by the Study Investigator as per standard 
medical/clinical judgment.
CT/MRI 
Contrast-enhanced Computed Tomography (CT) scans acquired on dedicated CT equipment is 
preferred for this study. CT with contrast of the chest, abdomen and pelvis are to be performed 
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for tumor assessments at baseline and beginning 6 weeks (+/- 1 week) from first dose and 
continuing every 6 weeks (+/- 1 week) for the first 24 weeks and every 12 weeks (+/- 1 week) 
thereafter, while on treatment or on treatment hold for any reason until disease progression and 
treatment discontinuation, whichever occurs later.  Additionally, with the exception of crossover 
participants, tumor assessments will not be required upon initiation of  subsequent anti-cancer 
therapy. 
CT scans should be acquired with 5mm slices with no intervening gap (contiguous). Although a 
contrast enhanced CT in particular for the chest is the preferred technique, a contrast enhanced 
MRI may be used based on local standards.
Should a subject have a contraindication for CT IV contrast, a non-contrast CT of the chest and a 
contrast enhanced MRI of the abdomen and pelvis may be obtained. MRI’s should be acquired 
with slice thickness of £5 mm with no gap (contiguous). 
Every attempt should be made to image each subject using an identical acquisition protocol on 
the same scanner for all imaging time points.
Note: Use of CT component of a PET/CT scanner:
Combined modality scanning such as with FDG-PET/CT is increasingly used in clinical care, 
and is a modality/technology that is in rapid evolution; therefore, the recommendations outlined 
here may change rather quickly with time. At present, low dose or attenuation correction CT 
portions of a combined FDG-PET/CT are of limited use in anatomically based efficacy 
assessments and it is therefore suggested that they should not be substituted for dedicated 
diagnostic contrast enhanced CT scans for anatomically based RECIST measurements. However, 
if a site can document that the CT performed as part of a FDG-PET/CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast) then the CT portion of the FDG-PET/CT 
can be used for RECIST 1.1measurements. Note, however, that the FDG-PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially
performed.
MRI Brain
MRI or CT of brain is required at screening in order to rule out active metastatic disease. For 
patients with a history of known brain metastasis, an MRI brain is required at baseline. A CT 
brain is not allowed for patients with known brain metastasis at baseline. Subjects with a history 
of brain metastasis should have surveillance MRI approximately every 12 weeks, or sooner if 
clinically indicated.
5.4
Efficacy Assessments
Study evaluations will take place in accordance with the flow charts in Section 5.1. Baseline 
assessments should be performed within 28 days prior to the first dose utilizing CT or MRI. In 
addition to chest, abdomen, pelvis, and brain, all known sites of disease should be assessed at 
baseline. Subsequent assessments should include chest, abdomen, and pelvis, and all known sites 
of disease and should use the same imaging method as was used at baseline. Subjects will be 
evaluated for tumor response beginning 6 weeks (1 week) from first dose and continuing every 
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6 weeks (1 week) for the first 24 weeks and every 12 weeks (1 week) thereafter, while on 
treatment or on treatment hold for any reason until disease progression and treatment 
discontinuation, whichever occurs later.  Additionally, with the exception of crossover 
participants, tumor assessments will not be required upon initiation of subsequent anti-cancer 
therapy. Tumor assessments for ongoing study treatment decisions will be completed by the 
investigator using RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria 
(Appendix 3).
5.4.1
Primary Efficacy Assessment
The primary endpoint is objective response rate (ORR) in all assigned subjects as determined by 
the investigators. ORR is defined as the number of subjects with a best overall response (BOR) 
of complete response (CR) or partial response (PR) divided by the number of assigned subjects. 
The investigator-determined ORR will be further characterized by the investigator-determined 
duration of response (DOR) and the magnitude of reduction in tumor volume. ORR and DOR 
will be assessed by BICR in selected tumor types.
5.4.2
Best Overall Response
The best overall response is determined once all the data for the subject is known. It is defined as 
the best response designation, as determined by the investigator or BICR for selected tumor 
types, recorded between the date of first treatment and the date of objectively documented 
progression per RECIST1.1 or the date of subsequent therapy, whichever occurs first. For 
subjects without documented progression or subsequent therapy, all available response
designations will contribute to the BOR assessment. 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.
Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point (minimum 4 weeks after criteria of objective response are first met). In 
this circumstance, the best overall response can be interpreted as in Table 5.4.2-1.
Table 5.4.2-1:
Best overall response when confirmation of CR and PR required
Overall Response 
First Timepoint
Overall Response 
Subsequent Timepoint
Best Overall response
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
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Table 5.4.2-1:
Best overall response when confirmation of CR and PR required
Overall Response 
First Timepoint
Overall Response 
Subsequent Timepoint
Best Overall response
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
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable.
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). 
Best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not 
CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best 
response is PR.
For purposes of this study, the minimum scan time from baseline for determination of SD will be 
6 weeks.
5.4.3
Duration of Objective Response
The duration of objective response is measured from the time measurement criteria are first met 
for confirmed CR/PR (whichever is first recorded) until the first date that progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study).
5.4.4
Immune related Response Criteria
Immune related response criteria using unidimensional measurements may be used to describe 
tumor shrinkage following RECIST 1.1 defined disease progression.76 The methodology is the 
same as described above for RECIST 1.1 except for:

New lesions do not automatically denote disease progression

The measurement of longest diameter of new measurable lesions are in included in the sum 
of the measurements of the original target lesions.
Best immune related responses, for subjects who have progression followed by tumor shrinkage 
are classified as irCR (disappearance of all lesions) or irPR (30% reduction from baseline).
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5.5
Pharmacokinetic Assessments
Serum samples for nivolumab and ipilimumab PK and immunogenicity assessments will be 
collected for all subjects.
5.5.1
Pharmacokinetics: Collection and Processing
A detailed schedule of PK and immunogenicity evaluations is provided in Table 5.5.1-1, Table 
5.5.1-2, and Table 5.5.1-3. All timepoints are relative to the start of study drug administration. 
Pre-dose samples should be taken within 30 minutes prior to the start of the first infusion for the 
day (prior to the nivolumab dose). All on-treatment PK timepoints are intended to align with 
days on which study drug is administered, if dosing occurs on a different day due to minor 
scheduling shifts, the PK sampling should be adjusted accordingly. If PK and immunogenicity 
samples are drawn but study drug(s) is not administered on the same day, samples will be 
retained and analyzed as planned. There is no need to collect another sample when the dose is 
resumed. Further details of sample collection, processing, and shipment will be provided in the 
laboratory procedures manual.
Table 5.5.1-1:
Pharmacokinetic & Immunogenicity Sampling Schedule - Arm N-I
(Dose level 2 and 2b)
Study Daya
Event
Time 
(Relative 
to Start of 
Infusion)
Hour: Min
Nivolumab 
PK
Blood 
Sample
Nivolumab 
Immunogenicity
Sample
Ipilimumab 
PK
Blood 
Sample
Ipilimumab 
Immunogenicity
Sample
D1 Week 1
Predoseb
00:00
X
X
X
X
D1 Week 4
Predose
00:00
X
X
X
X
D1 Week 10
Predose
00:00
X
X
X
X
D1 Week 13
Predose
00:00
X
X
D1 Week 25
Predose
00:00
X
X
Day 1 of every 
16th week 
until 
discontinuation 
of study 
treatment or 
completion of 
2 years of 
study 
treatment
Predose
00:00
X
X
a
If ipilimumab is discontinued and nivolumab continues, ipilimumab PK and Immunogenicity should be 
collected only for the next 2 timepoints (corresponding to ipilimumab sample collection) according to the PK table. 
If ipilimumab is discontinued, nivolumab will follow the same schedule as originally planned for that subject.
b Predose samples for nivolumab and ipilimumab should both be collected prior to start of nivolumab infusion 
(preferably within 30 minutes). If the infusion is delayed and a pre-dose sample is already collected, there is no 
need to collect an additional pre-dose sample.
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Table 5.5.1-2:
Pharmacokinetic & Immunogenicity Sampling Schedule - Arm N
Study Day
Event
Time 
(Relative to 
Start of 
Infusion)
Hour: Min
Nivolumab 
PK
Blood 
Sample
Nivolumab 
Immunogenicity
Sample
Ipilimumab 
PK
Blood 
Sample
Ipilimumab 
Immunogenicity
Sample
All Subjects in Arm N
D1 Week 1
Predose
00:00
X
X
D1 Week 3
Predose
00:00
X
X
D1 Week 5
Predose
00:00
X
X
D1 Week 13
Predose
00:00
X
X
Day 1 of every 
16th week until 
discontinuation 
of study 
treatment or 
completion of 2 
years of study 
treatment
Predose
00:00
X
X
Crossover Subjects Only (SCLC subjects from the expansion cohorts under or after Amendment 09 are 
excluded from this option)
Crossover D1 
Week 1
Predosea
00:00
X
X
X
X
Crossover D1 
Week 4
Predose
00:00
X
X
X
X
Crossover D1 
Week 10
Predose
00:00
X
X
X
X
Crossover D1 
Week 13
Predose
00:00
X
X
Crossover D1 
Week 25
Predose
00:00
X
X
Day 1 of every 
16th week until 
discontinuation 
of study 
treatment or 
completion of 2 
years of study 
treatment
Predose
00:00
X
X
a Predose samples for nivolumab and ipilimumab should both be collected prior to start of nivolumab infusion 
(preferably within 30 minutes). If the infusion is delayed and a pre-dose sample is already collected, there is no 
need to collect an additional pre-dose sample.
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Table 5.5.1-3:
Pharmacokinetic & Immunogenicity Sampling Schedule - Arm N-I 
(Dose level 2c)
Study Daya
Event
Time 
(Relative 
to Start of 
Infusion)
Hour: Min
Nivolumab 
PK
Blood 
Sample
Nivolumab 
Immunogenicity
Sample
Ipilimumab 
PK
Blood 
Sample
Ipilimumab 
Immunogenicity
Sample
D1 Week 1
Predoseb
00:00
X
X
X
X
D1 Week 7
Predose
00:00
X
X
X
X
D1 Week 19
Predose
00:00
X
X
X
X
After Week 19 
Day 1, Day 1 
of every 18th 
week until 
discontinuation 
of study 
treatment or 
completion of 
2 years of 
study 
treatment
Predose
00:00
X
X
X
X
a If ipilimumab is discontinued and nivolumab continues, ipilimumab PK and Immunogenicity should be collected 
only for the next 2 timepoints (corresponding to ipilimumab sample collection) according to the PK table
b Predose samples for nivolumab and ipilimumab should both be collected prior to start of nivolumab infusion 
(preferably within 30 minutes). If the infusion is delayed and a pre-dose sample is already collected, there is no 
need to collect an additional pre-dose sample.
 
 
 
 
 
 
 
 
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5.7
Outcomes Research Assessments
General health status will be measured using the EQ-5D. The EQ-5D is a standardized 
instrument for use as a measure of self-reported general health status. The EQ-5D comprises of 
5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety) and a visual 
analog rating scale (VAS). The utility data generated from the EQ-5D is recommended for and 
commonly used in cost effectiveness analysis.
The EQ-5D measure will be collected as follows:

Nivolumab monotherapy arm: Collect prior to each study drug administration at Week 1, 3, 
5, 7, 9, 11, and 13, then at the same time of subsequent tumor assessments, during 
Follow Up 1 and 2 and survival visits.

Nivolumab / Ipilimumab combination arm: Collect prior to each study drug administration at 
Week 1, 4, 7, 10, and 13, then at the same time of subsequent tumor assessments, during 
Follow Up 1 and 2 and survival visits.

The EQ-5D can be done via a phone contact when a clinic visit is not feasible (ie, follow up 
scans are being done at another facility or department) in order to not miss the assessment.
5.8
Other Assessments 
 
 
 
 
 
 
5.8.2
Pharmacogenetic Research
Pharmacogenetic sample collection will be performed at sites that permit pharmacogenetic 
studies to be conducted in compliance with all applicable laws, rules, and regulations. To 
participate in the Pharmacogenetic Sample Amendment, subjects must provide a signed 
Pharmacogenetic Blood DNA informed consent and must have consented to participate in this 
main clinical trial. Please refer to Amendment 01 and 07 for further information.
5.8.3
Demographics and Medical History
At Screening, information regarding subject’s demographics and medical history including date 
of birth, gender, race and ethnicity, general medical history, tobacco use, potential risk factors 
for pulmonary related events, disease diagnosis including diagnosis itself, date of initial 
diagnosis, disease stage at initial diagnosis, cell type, disease classification for SCLC only, 
current disease diagnosis with date and stage, HER-2 status, receptor status, prior surgery, 
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radiotherapy, and all prior lines of systemic cancer therapies with agents, start and stop dates, 
best response to the therapy and date of progression after each treatment line will be collected. 
For SCLC and ovarian cancer subjects, evaluation of platinum-free interval (PFI) from the 
completion of any platinum-based chemotherapy and subsequent disease progression, and 
Treatment-free-interval (TFI) from the completion of any other cytotoxic or targeted based prior 
treatment line and subsequent disease progression will be collected. For ovarian cancer, 
information about BRCA and Homologous Recombinant Deficiency (HRD), if available, will be 
collected.
5.9
Blinded Independent Central Review (BICR)
A Blinded Independent Central Review (BICR) will be performed for randomized subjects in 
selected tumor types to determine RECIST 1.1 response for the analysis of ORR, DOR, and PFS.
Details of the Imaging responsibilities and procedures will be specified in the Imaging charter.
Sites will be informed of quality issues or the need for repeat scanning via queries from the 
central imaging vendor. Results of Central Imaging analysis will not be returned to the site.
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.)
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6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect 

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.) Potential drug induced liver injury (DILI) is also considered an 
important medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. 
(See Section 6.1.1 for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into the 
study. Appropriate documentation is required in these cases
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
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)

hospitalizations for the administration of subsequent anticancer therapy.
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 must be collected that occur during the screening period 
and within 100 days of discontinuation of dosing. Subjects who are randomized but never treated 
with study drug, must have SAEs collected for 30 days from the date of randomization. If 
applicable, SAEs must be collected that relate to any later protocol-specified procedure 
(eg, a follow-up skin biopsy).
The investigator should report any SAE that occurs after these time periods and that is believed 
to be related to study drug or protocol-specified procedure.
An SAE report should be completed for any event where doubt exists regarding its seriousness.
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship 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 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 BMS (or designee) 
using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
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6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects. 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 
as appropriate. All identified nonserious AEs must be recorded and described on the nonserious 
AE page of the CRF (paper or electronic). 
All nonserious adverse events (not only those deemed to be treatment-related) should be 
collected continuously during the treatment period and for a minimum of 100 days following the 
last dose of study treatment.
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which 
were exacerbated by the induction of autoimmunity. Information supporting the assessment will 
be collected on the subject’s case report form.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an SAE 
specified as follows:

Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted

Any laboratory test result abnormality that required the subject to receive specific 
corrective therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of study exposure, including during at 
least 5 half lives after product administration, the investigator must immediately notify the BMS 
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(or designee) Medical Monitor of this event and complete and forward a Pregnancy Surveillance 
Form to BMS (or designee) within 24 hours and in accordance with the SAE reporting 
procedures described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug, after a thorough 
discussion of benefits and risk with the subject.
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 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as SAEs (see Section 6.1.1 for reporting details).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential drug induced liver injury is defined as: 
1. ALT or AST elevation > 3 times upper limit of normal (ULN)
AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND 
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic. 
6.7
Other Safety Considerations
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
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by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly. 
6.8
Safety Assessments
Safety assessments including targeted physical examination, vital signs and oxygen saturation, 
physical measurements including weight and ECOG performance status, and laboratory tests 
including Cell Blood Count (CBC) with differential, Liver Function Tests (LFTs), Blood Urea 
Nitrogen (BUN) or serum urea level, creatinine, albumin, Ca, Mg, Na, K, Cl, LDH, glucose, 
amylase, lipase, TSH (if TSH result is abnormal, subsequent testing of Free T4 and Free T3 is 
required) will be conducted in each treatment cohort as specified in the flow chart in section 5.1.
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
Ipilimumab has been studied in > 13,800 patients in clinical trials while nivolumab has been 
studied in more than 700 patients in clinical trials. The AE profile of nivolumab appears to be 
independent of tumor type. The safety of the combination of nivolumab and ipilimumab has been 
reported in 53 melanoma subjects and the spectrum of adverse events observed among patients 
treated with the concurrent regimen was qualitatively similar to previous experience with 
nivolumab or ipilimumab monotherapy. Adverse events observed with the combination therapy 
were manageable and generally reversible with the use of existing treatment algorithms. In 
addition, this is an open label study. Therefore, a data monitoring committee will not be utilized 
for this Phase 1/2 study.
The subjects’ safety will be monitored on an ongoing basis. Safety conference calls with 
investigators and representatives of the sponsor will be held approximately once a month with 
additional meetings as necessary. The BMS medical monitor is a physician responsible for 
reviewing, on a systematic and continuous basis, the safety of patients on this study. This 
includes a review of serious and non-serious adverse events, which includes all hematological 
and non-hematological events.
In addition, a BMS medical safety team (MST) routinely reviews safety signals across the entire 
nivolumab program including combination studies with ipilimumab. The MST is independent 
from the BMS medical monitor. The MST has the primary responsibility within Bristol-Myers 
Squibb for assessing emerging safety trends, identifying potential safety signals, notifying 
appropriate stakeholders of relevant findings, and implementing risk management plans.
The MST is responsible for reviewing data from all sources including non-clinical studies and 
clinical trials, monitoring the progress of various nivolumab safety support activities, and 
recommending and implementing necessary changes to the safety plan and any other specific 
safety-related activities.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
Sample Size determination in the original protocol
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This study comprises a Dose Escalating Safety Evaluation Phase for the Combination Arm, 
followed by a Staged Enrollment for Arm N and Arm N-I. 
In the original protocol, gastric cancer, SCLC, TNBC, and pancreatic cancer are included and the 
Staged Enrollment Part utilizes a modified Simon two-stage design79 with the treatment of 40 
subjects to evaluate whether nivolumab or the combination of nivolumab/ipilimumab yields an 
objective response rate (ORR) that is of clinical interest. In this study, an ORR of 10% or less is 
considered not of clinical value, and an ORR of 25% or greater is considered of strong clinical 
interest. The modified Simon design evaluates the null hypothesis that the true response rate is 
10% versus the alternative hypothesis that the true response rate is > 10%. The 2-stage testing 
within each cohort targets a Type I error rate of 5% and has 80% power to reject the null 
hypothesis if the true response rate is 25%. 
Sample Size determination for bladder cancer cohort
In Amendment 06, the bladder cancer cohort is added. A one stage design with the treatment of 
60-100 subjects is used. These sample sizes provide 90% to 97% power to reject the null 
hypothesis of a 10% response rate if the true response rate is 25% with a two-sided Type I error 
rate of 5%. 
Sample Size determination for SCLC expansion cohort:
In Amendment 09, in addition to the original two-stage design in the SCLC cohort, additional 
SCLC expansion cohort subjects will be randomized in a 3:2 ratio to one of two expansion 
groups: Arm A (150 subject, nivolumab mono 3 mg/kg q2w) or Arm B (100 subjects, nivolumab 
1 mg/kg + ipilimumab 3 mg/kg q3w) and will be stratified by number of prior treatment lines (1 
vs 2 prior chemotherapy regimens).
Based on SCLC data so far observed in this study with an ORR of about 10% for nivolumab 
monotherapy and about 23% for the nivolumab + ipilimumab combination therapy, sample sizes
of N = 150 for nivolumab monotherapy and N = 100 for nivolumab + ipilimumab combination 
therapy (nivolumab 1 mg/kg + ipilimumab 3 mg/kg) will target a Type I error rate of 5% 
(two-sided) and will have 78% power to detect the difference between these two arms if the true 
response rates are 10% and 23%, respectively. 
Sample Size determination for ovarian cancer cohort
Also in Amendment 09, an ovarian cancer cohort is added and one stage design with the 
treatment of 40 subjects for each combination arm will be used. These sample sizes will provide 
79% power to reject the null hypothesis of 10% response rate, if the true response rate is 25% 
with a two-sided Type I error rate of 5%. 
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8.2
Populations for Analyses

All Enrolled Subjects: All subjects who signed an informed consent form and were registered 
into the IVRS.

All Assigned Subjects: All subjects who were assigned to the highest tested tolerated dose 
level in the Dose Escalating Safety Evaluation Phase or to any treatment group during the 
Staged Enrollment Phase. 

All Treated Subjects: All subjects who received at least one dose of any study medication.

All PK Subjects: All assigned subjects with available serum time-concentration data.

All Immunogenicity Subjects: All treated subjects with baseline and at least 1 post baseline 
immunogenicity assessment.

All Crossover Subjects: All treated subjects who crossed over from Arm N to Arm N-I.
SCLC subjects from the expansion cohorts under or after Amendment 09 are excluded from 
the crossover option.

All PD-L1 tested subjects: All subjects who had a tumor tissue sample available for 
assessment of PD-L1 expression at baseline.

All treated, PD-L1 tested subjects: All PD-L1 tested subjects who received at least one dose 
of study treatment.

All PD-L1 evaluable subjects: All treated PD-L1 tested subjects with quantifiable PD-L1 
expression.
*Those subjects in the Dose Escalation Safety Evaluation Phase who received at least one dose 
of the highest dose level confirmed for further investigation will be counted as part of the 
required 18 treated subjects for Stage 1. In addition to being included in the All Treated Subjects 
population, those subjects will also be included in the All Dose Escalation Subjects population. 
Those subjects in the Dose Escalation Safety Evaluation Phase who received at least one dose of 
a dose level that was not confirmed for further investigation will not be included in the All 
Treated Subjects population.
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary endpoint is the objective response rate (ORR). The ORR is defined as the number of 
subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) 
divided by the number of treated subjects. The BOR is defined as the best response designation, 
as determined by the investigator or BICR for selected tumor types, recorded between the date of
randomization or treatment assignment and the date of objectively documented progression per 
RECIST 1.1 or the date of subsequent anti-cancer therapy, whichever occurs first. CR or PR 
determinations included in the BOR assessment must be confirmed by a second scan no less than 
4 weeks after the criteria for response are first met. For subjects without documented progression 
or subsequent therapy, all available response designations will contribute to the BOR assessment. 
For subjects who continue treatment beyond progression, the BOR should be determined based 
on response designations recorded up to the time of the initial RECIST 1.1-defined progression.
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For the SCLC expansion cohort, the estimated difference along with its corresponding p-value of 
ORR assessed by BICR between nivolumab monotherapy and nivolumab / ipilimumab 
combination therapy (nivolumab 1 mg/kg + ipilimumab 3 mg/kg) will be provided. In addition, 
95% CI (two-sided) will also be presented for the estimated difference of ORR between 
nivolumab monotherapy and nivolumab / ipilimumab combination therapy.
Similar methods will be used to summarize ORR for each stratification factor (no p-value will be 
provided).
ORR will be further characterized by the duration of response (DOR) and the magnitude of 
reduction in tumor volume. DOR will be computed for subjects with a BOR of PR or CR and is 
defined as the time from first confirmed response (CR or PR) to the date of the first documented 
tumor progression as determined using RECIST 1.1 criteria or death due to any cause, whichever 
occurs first. For subjects who neither progress nor die, the DOR will be censored using the same 
censoring algorithm as used for PFS in Section 8.3.2. The magnitude of reduction in tumor 
volume is defined as the percent decrease in tumor volume from baseline to nadir, observed up 
until the time of the first documented tumor progression or death.
These measures of response will be interpreted in the context of historical responses observed 
following treatment with approved agents.
8.3.2
Secondary Endpoint(s)
The secondary objective (to assess the safety and tolerability of nivolumab monotherapy or 
nivolumab combined with ipilimumab in subjects with advanced or metastatic tumors) will be 
primarily assessed by the rate of treatment-related AEs leading to drug discontinuations during 
the first 12 weeks of treatment. In addition, safety and tolerability will be analyzed through the 
incidence of adverse events, serious adverse events, and specific laboratory abnormalities 
(worst grade) in each cohort. Toxicities will be graded using the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
PFS is defined as the time from treatment assignment in IVRS to the date of the first documented 
tumor progression, as determined by the investigator or BICR for selected tumor types (per
RECIST 1.1), or death due to any cause, whichever occurs first. Subjects who die without a 
reported prior progression will be considered to have progressed on the date of their death. 
Subjects who did not progress or die will be censored on the date of their last evaluable tumor 
assessment. Subjects who did not have any on-study tumor assessments and did not die will be
censored on the date they were assigned treatment in the IVRS. Subjects who started anti-cancer 
therapy either prior to death or without a prior reported progression will be censored on the date 
of their last evaluable tumor assessment prior to the initiation of subsequent anti-cancer therapy.
OS is defined as the time between the date of treatment assignment in IVRS and the date of death 
due to any cause. A subject who has not died will be censored at the last known alive date. 
OS will be followed continuously while subjects are on the study drug and every 3 months via 
in-person or phone contact after subjects discontinue the study drug.
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index.
8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Demographic and baseline characteristics will be summarized in all treated subjects by cohort, as 
randomized or assigned, using descriptive statistics.
8.4.2
Efficacy Analyses
8.4.2.1
Primary Endpoint Methods
The efficacy analyses will be performed on the all treated population. ORR will be summarized 
for each cohort by a binomial response rate and corresponding two-sided 95% exact CI using the 
method proposed by Atkinson and Brown80 for cohorts using the two-stage design and the 
Clopper-Pearson method for cohorts using the one-stage design81. 
For SCLC expansion cohort, the estimated difference along with its corresponding p-value of 
ORR assessed by BICR between nivolumab monotherapy and nivolumab/ipilimumab 
combination therapy (nivolumab 1 mg/kg + ipilimumab 3 mg/kg) will also be presented with 
95% CI. Similar methods will be used to summarize ORR for each stratification factor. However 
the p-value will not be provided for each stratification factor.
DOR as determined by the investigator or BICR for selected tumor types will be summarized for
subjects who achieve confirmed PR or CR using the Kaplan-Meier (KM) product-limit method. 
The median value, along with two-sided 95% CI using the Brookmeyer and Crowley method,
will also be calculated by cohort. In addition, the percentage of responders still in response at 
different time points (3, 6, and 12 months) will be presented based on the KM plot.
The magnitude of reduction in tumor burden will be summarized descriptively. Immune related 
responses will be summarized descriptively.
8.4.2.2
Secondary Endpoint Methods
PFS and OS will be summarized descriptively using Kaplan-Meier methodology. Median values 
of PFS and OS, along with two-sided 95% CIs using the Brookmeyer and Crowley method, will 
be calculated for each cohort. PFS rates at 6 and 12 months, and OS rates at 12 and 24 months 
will also be estimated. Associated two-sided 95% CIs will be calculated using the Greenwood 
formula. Additional survival analysis may be conducted for up to 5 years beyond analysis of the 
primary endpoint.
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.
8.4.3
Safety Analyses
Safety analyses will be performed in all treated subjects. Descriptive statistics of safety will be 
presented using National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0. All on-study AEs, Grade 3-4 AEs, treatment-related AEs, 
Grade 3-4 treatment-related AEs, SAEs, treatment-related SAEs, and AEs leading to 
discontinuation will be tabulated using worst grade per NCI CTCAE v 4.0 criteria by system 
organ class and preferred term. On-study lab parameters including hematology, chemistry, liver 
function, and renal function and Grade 3-4 Lab Abnormalities will be summarized using worst 
grade NCI CTCAE v 4.0 criteria.
8.4.4
Pharmacokinetic Analyses
The nivolumab and ipilimumab concentration data obtained in this study may be combined with 
data from other studies in the clinical development program to develop or refine a population PK 
model. This model will be used to evaluate the effects of intrinsic and extrinsic covariates on the 
PK of nivolumab and ipilimumab and to determine measures of individual exposure (such as 
steady-state peak, trough, and time-averaged concentration). In addition, model determined 
exposures may be used for exposure-response analyses. Results of population PK and exposure 
response-analyses will be reported separately.
8.4.6
Outcomes Research Analyses
Subject’s overall health state on a visual analog scale (EQ-VAS) at each assessment time point 
will be summarized using descriptive statistics by treatment arm (N and N-I), as randomized or 
assigned.
Proportion of subjects reporting problems for the 5 EQ-5D dimensions at each assessment time 
point will be summarized by level of problem and by treatment group, as randomized or 
assigned. Percentages will be based on number subjects assessed at assessment time point.
A by-subject listing of EQ-5D with the problem levels for each of the 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort and anxiety/depression), health state 
(5 dimensions digits combined in a 5-digit number) and EQ-VAS will be provided.
 
 
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8.5
Interim Analyses
Data will be reviewed during the Dose Escalation Safety Evaluation Phase to determine the 
maximum tolerated dose level for arm N-I and to make decisions about Stage 2 for each cohort
using Simon’s 2-stage design. The decision to proceed from Stage 1 to Stage 2 will be conducted 
for each tumor type and for each treatment arm independently.
An interim analysis may be conducted after Stage 1, by cohort. This interim analysis may be 
triggered if a “super” response (ie, 8 or more responders out of 18 subjects) is observed or if it is 
necessary in order to make decisions regarding further development. Summaries and listings of 
efficacy and safety will be provided. This interim analysis will not impact the study duration and 
the trial will continue as planned.
Interim analyses may be conducted for supporting internal decision making or for external data 
disclosure purposes by cohort, depending upon the maturity of the data.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
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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. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product (those supplied by BMS) is maintained at each study site where study 
drug are 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 identification number or batch number 

amount dispensed to and returned by each subject, including unique subject identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable
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
amount returned to BMS

retain samples for bioavailability/bioequivalence, if applicable 

dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the paper or electronic SAE form and Pregnancy Surveillance form, respectively. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator 
and who is delegated this task on the Delegation of Authority Form For electronic CRFs, review 
and approval/signature is completed electronically through the BMS electronic data capture tool. 
The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected considering the following criteria:

External Principal Investigator designated at protocol development

National Coordinating Investigator 

Study Steering Committee chair or their designee
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
Subject recruitment (eg, among the top quartile of enrollers)

Involvement in trial design

Regional representation (eg, among top quartile of enrollers from a specified region or 
country)

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study require approval by BMS prior to publication or presentation 
and must adhere to BMS’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 BMS at the earliest practicable time for review, but 
at any event not less than 30 days before submission or presentation unless otherwise set forth in 
the CTA. BMS 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 BMS 
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 (eg, Investigator Brochure for 
an unapproved investigational product)
Serious Adverse Event
Serious adverse event 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 have caused 
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
Term
Definition
AE
adverse event
ACLS
advanced cardiac life support
AI
accumulation index
AI_AUC
AUC Accumulation Index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Cmax
Cmax Accumulation Index; ratio of Cmax at steady state to Cmax after 
the first dose
AI_Ctau
Ctau Accumulation Index; ratio of Ctau at steady state to Ctau after the 
first dose
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
A-V
Atrioventricular
-HCG
beta-human chorionic gonadotrophin
BA/BE
bioavailability/bioequivalence
BC
Breast cancer
BCRA1
Breast cancer type 1
%BE
percent biliary excretion
BICR
Blinded Independent Central Review
BID, bid
bis in die, twice daily
BLQ
below limit of quantification 
BMI
body mass index
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Term
Definition
BMS
Bristol-Myers Squibb
BP
blood pressure
BRt
Total amount recovered in bile
%BRt
Total percent of administered dose recovered in bile
BUN
blood urea nitrogen
C
Celsius
C12
concentration at 12 hours
C24
concentration at 24 hours
Ca++
Calcium
CAV
cyclophosphamide, doxorubicin and vincristine
Cavg
average concentration
CBC
complete blood count
Cexpected-tau
expected concentration in a dosing interval
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
Chloride
CLcr
creatinine clearance
CLD
Dialysate clearance of drug from plasma/serum
CLNR
nonrenal clearance
CLR
renal clearance
CLT
total body clearance
CLT/F (or CLT)
apparent total body clearance
CLT/F/fu or 
CLT/fu
Apparent clearance of free drug or clearance of free if (if IV)
cm
Centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CNS
Central nervous system
CR
Complete response
CRC
Clinical Research Center
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Term
Definition
CRF
Case Report Form, paper or electronic
CT
Computed tomography
Ct
Expected concentration at a certain time, usually at the end of an 
expected future dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctau
Concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
CTLA-4
Cytotoxic T-lymphocyte-associated protein 4
Ctrough
Trough observed plasma concentration
CV
coefficient of variation
CYP
cytochrome p-450
D/C
Discontinue
DCR
Disease control rate
dL
Deciliter
DLT 
Dose limiting toxicity
DOR
Duration of response
DRt
Total amount recovered in dialysate
%DRt
Total percent of administered dose recovered in dialysate
DSM IV
Diagnostic and Statistical Manual of Mental Disorders (4th Edition)
EA
extent of absorption
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
ED
Extensive disease
EDC
Electronic Data Capture
EEG
electroencephalogram
eg
exempli gratia (for example)
EMA
European Medicinal Agency
EOI
End of Infusion
EQ-5D
EuroQol 5 Dimensions Questionnaire
ER
Estrogen receptor
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Term
Definition
ESR
Expedited Safety Report
EU
European Union
F
Bioavailability
Fb
fraction of bound drug
FDA
Food and Drug Administration
FFPE
Formalin-fixed, paraffin-embedded
FI
fluctuation Index ([Cmax-Ctau)/Cavg])
FIGO
Federation of Gynecology and Obstetrics
FOLFIRINOX
combination of 5-FU, leucovorin, irinotecan, oxaliplatin
FRt
total amount recovered in feces
%FRt
total percent of administered dose recovered in feces
FSH
follicle stimulating hormone
%FE
percent fecal excretion
fu
fraction of unbound drug
FU1
Follow-up 1
FU2
Follow-up 2
g
Gram
GC
gas chromatography
GC
Gastric cancer
GCP
Good Clinical Practice
G criteria
adjusted R2 value of terminal elimination phase
GEJ
Gastro-esophageal junction
GEM
Gemcitabine
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
h
Hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCO3-
Bicarbonate
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Term
Definition
HER-2
Human epidermal growth factor receptor 2
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HR
heart rate
HRD
homologous recombinant deficiency
HRT
hormone replacement therapy
IB
Investigator Brochure
IC
Informed Consent
ICD
International Classification of Diseases
ICF
Informed consent form
ICH
International Council for Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IFN
Interferon
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
irCR
Immune related complete response
irPR
Immune related partial response
irPD
Immune related progression
IU
International Unit
IV
Intravenous
K
slope of the terminal phase of the log concentration-time curve
K3EDTA
potassium ethylenediaminetetraacetic acid
K+
Potassium
kg
Kilogram
KM
Kaplan-Meier
z
terminal disposition rate constant
L
Liter
LC
liquid chromatography
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Term
Definition
LD
Limited disease
LDH
lactate dehydrogenase
LFT
Liver function test
ln
natural logarithm
Lz_Start
The time point starting the log-linear elimination phase defining the 
terminal half life
Lz_End
The time point ending the log-linear elimination phase defining the 
terminal half life
Lz_N
Number of time points in the log-linear elimination phase defining the 
terminal half life
MST
medical safety team
mg
Milligram
Mg++
Magnesium
MIC
minimum inhibitory concentration
min
Minute
mIU/ml
Milli international units per millimeter
mL
Milliliter
mmHg
millimeters of mercury
mOS
Median overall survival
mRCC
Metastatic renal cell carcinoma
MR_AUC(0-T)
Ratio of metabolite AUC(0-T) to parent AUC(0-T), corrected for 
molecular weight
MR_AUC(INF)
Ratio of metabolite AUC(INF) to parent AUC(INF), corrected for 
molecular weight
MR_AUC(TAU)
Ratio of metabolite AUC(TAU) to parent AUC(TAU), corrected for 
molecular weight
MR_Cmax
Ratio of metabolite Cmax to parent Cmax, corrected for molecular 
weight
MR_Ctau
Ratio of metabolite Ctau to parent Ctau, corrected for molecular weight
MRI
Magnetic resonance imaging
MRT
mean residence time
MS
mass spectrometry
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Term
Definition
MTD
maximum tolerated dose
g
Microgram
N
number of subjects or observations
N
Nivolumab monotherapy
N-I
Nivolumab in combination with Ipilimumab
Na+
Sodium
N/A
not applicable
NCCN
National Comprehensive Cancer Network
NCI CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse 
Events
ng
Nanogram
NIMP
non-investigational medicinal products 
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
Non-small cell lung cancer
ORR
Overall response rate
OS
Overall survival
PAC
Paclitaxel
PARP
Poly (ADP-ribose) polymerase
pAUCe
Extrapolated partial AUC from last quantifiable concentration to infinity
Pb
percent of bound drug
PBMC
Peripheral blood mononuclear cell
PC
Pancreatic cancer
pCR
Complete pathological response
PD
Pharmacodynamics
PD-1
Programmed death 1
PDL-1
Programmed cell death 1 ligand 1
PE
Physical Exam
PE
Platinum plus etopiside
PFI
platinum-free interval
PFS
Progression Free Survival
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Term
Definition
PK
Pharmacokinetics
PO
per os (by mouth route of administration)
PR
Partial response
PR
Progesterone receptor
PS
Performance status
PT
prothrombin time
PTT
partial thromboplastin time
Pu
percent of unbound drug
Q2W
Every two weeks
Q3W
Every three weeks
QC
quality control
QD, qd
quaque die, once daily
R2
coefficient of determination
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RT-PCR
Reverse transcription-polymerase chain reaction
SAE
serious adverse event
SCLC
Small cell lung cancer
SD
stable disease
SD
standard deviation
SOC
Standard of care
SOP
Standard Operating Procedures
sp.
Species
Subj
Subject
t
Temperature
T
Time
TAO
Trial Access Online, the BMS implementation of an EDC capability
TEN
toxic epidermal necrolysis
TFI
Treatment-free-interval
T-HALF
Half life
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Term
Definition
T-HALFeff_AUC
Effective elimination half-life that explains the degree of AUC 
accumulation observed
T-HALFeff_Cmax
Effective elimination half-life that explains the degree of Cmax 
accumulation observed)
TID, tid
ter in die, three times a day
Tmax, TMAX
time of maximum observed concentration
TNBC
Triple negative breast cancer
TPC
Treatment of physician’s choice
TR_AUC(0-T)
AUC(0-T) treatment ratio
TR_AUC(INF)
AUC(INF) treatment ratio
TR_Cmax
Cmax treatment ratio
UR
urinary recovery
%UR
percent urinary recovery
URt
total amount recovered in urine
US
United States
%URt
total percent of administered dose recovered in urine
UV
Ultraviolet
Vss/F (or Vss)
apparent volume of distribution at steady state
Vz
Volume of distribution of terminal phase (if IV and if multi-exponential 
decline)
W
Washout
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
x g
times gravity
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APPENDIX 1
PERFORMANCE STATUS SCALES
STATUS
SCALES
STATUS
KARNOFSKY
ZUBROD-
ECOG-WHO
Normal, no complaints
100
0
Normal activity
Able to carry on normal activities Minor 
signs or symptoms of disease
90
0
Symptoms, but fully 
ambulatory
Normal activity with effort
80
1
Cares for self. Unable to carry on 
normal activity or to do active work
70
1
Symptomatic, but in bed 
< 50% of the day.
Requires occasional assistance, but able 
to care for most of his needs
60
2
Requires considerable assistance and 
frequent medical care
50
2
Needs to be in bed > 50% of 
the day, but not bedridden
Disabled. Requires special care and 
assistance
40
3
Severely disabled. Hospitalization 
indicated though death non imminent
30
3
Very sick. Hospitalization necessary. 
Active supportive treatment necessary
20
4
Unable to get out of bed
Moribund
10
4
Dead
0
5
Dead
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APPENDIX 2
MANAGEMENT ALGORITHMS
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APPENDIX 3
RECIST 1.1
Changes in tumor measurements and tumor responses will be assessed by the investigator using 
the RECIST 1.1 (Response Evaluation Criteria in Solid Tumors) criteria. (Eisenhauer, et al 
2009.)
Source:  Eisenhauer et al New response evaluation criteria in solid tumours: Revised RECIST 
guideline (version 1.1), European Journal of Cancer, 2009, Vol. 45, p 228-247
1
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
To assess objective response or future progression, it is necessary to estimate the overall tumor
burden at baseline and 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 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows:
1.1
Measurable lesions
Measurable lesions must be 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 by CT/MRI scan - (CT/MRI scan slice thickness no greater than 5 mm)

10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable)

20 mm by chest x-ray

Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.
1.2
Non-measurable lesions

All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with 10 to < 15 mm short axis), as well as truly non-measurable lesions.  

Lesions considered truly 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.
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1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions

Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.

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 selection as target lesions.
1.3.3
Lesions with prior local treatment
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 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 28 days before the 
beginning of the treatment.
1.4.2
Method of assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
1.4.2.1
CT/MRI scan
CT/MRI is the best currently available and reproducible method to measure lesions selected for 
response assessment. Measurability of lesions on CT/MRI scan is based on the assumption that 
CT/MRI slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness.
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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 
aerated lung.
1.4.2.3
Clinical lesions 
Clinical lesions will only be considered measurable when they are superficial and 10 mm 
diameter as assessed using calipers. For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is suggested. As previously noted, 
when lesions can be evaluated by both clinical 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 not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. 
1.4.2.5
Endoscopy, laparoscopy
The utilization of these techniques for objective tumor evaluation is not advised.
1.4.2.6
Tumor markers 
Tumor markers alone cannot be used to assess objective tumor response.  
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 to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should lend themselves to reproducible repeated
measurements.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted below, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
2.1.1
Lymph nodes
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
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15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
Nodes that have a short axis < 10 mm are considered 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-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’. In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’).
3
TUMOR RESPONSE EVALUATION 
3.1
Evaluation of target lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
Partial Response (PR):  At least a 30% decrease in the sum of diameters of target lesions,
taking as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression).
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
3.1.1
Special notes on the assessment of target lesions
3.1.1.1
Lymph nodes
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
Nodes that have a short axis < 10 mm are considered 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 (eg, 2 mm). If the radiologist is 
able to provide an actual measurement, that should be recorded, even if it is below 5 mm.
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However, when such a lesion becomes difficult to assign an exact measure to then:

if it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm. 

if the lesion is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned (note: in case of a lymph node believed to be present and 
faintly seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well). This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).
3.1.1.3
Target lesions that split or coalesce on treatment

When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should 
be added together to calculate the target lesion sum. 

As lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced 
such that they are no longer separable, the vector of the longest diameter in this instance 
should be the maximal longest diameter for the ‘coalesced lesion’.
3.2
Evaluation of non-target lesions
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis).
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD):  Unequivocal progression of existing non-target lesions. (Note: the 
appearance of one or more new lesions is also considered progression).
3.2.1
Special notes on assessment of non-target lesions
The concept of progression of non-target disease requires additional explanation as follows:
3.2.1.1
When the subject also has measurable disease

To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. 

A modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to 
quality for unequivocal progression status.
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3.2.1.2
When the subject has only non-measurable disease

To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening such that the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. 

A modest ‘increase’ in the size of 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: ie, an increase in tumor burden representing 
an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, 
an increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as ‘sufficient to require a change in therapy’.

If ‘unequivocal progression’ is seen, the subject should be considered to have had overall PD 
at that point. 
3.2.1.3
Tumor markers
Tumor markers alone cannot be used to assess objective tumor responses. If markers are initially 
above the upper normal limit, however, they must normalize in order for a subject to be 
considered as having attained a complete response. 
3.3
New lesions  
The appearance of new malignant lesions denotes disease progression. The finding of a new 
lesion should be unequivocal: ie, not attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumor (for example, 
some ‘new’ bone lesions may be simply healing or flare of pre-existing lesions). This is 
particularly important when the 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 not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the subject who has visceral disease at baseline and while on study has a CT or MRI brain scan
ordered 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, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan.
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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 might be a sign of PD 
based on a new lesion. However, other reasons for newly detected lesions with increased 
FDG-PET uptake, such as inflammatory lymphnodes, should be taken into consideration.

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 positive
FDG-PET scan).

If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD.

Other reasons for newly detected lesions with increased FDG-PET uptake, such as 
inflammatory lymphnodes, should be taken into consideration.
4
RESPONSE CRITERIA
4.1
Time point response
A response assessment should occur at each time point specified in the protocol.
For subjects who have measurable disease at baseline Table 1 provides a summary of the 
overall response status calculation at each time point.
Table 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 or not all 
evaluated
No
PR
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Table 1:
Time point response: subjects with target (+/– non-target) disease.
Target lesions
Non-target lesions
New lesions
Overall response
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.
For subjects who have non-measurable (therefore non-target) disease only, Table 2 is to be 
used.
Table 2:
Time point response: Subjects with non-target disease only
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is 
not advised.
CR = complete response, PD = progressive disease, and NE = not evaluable.
4.1.1
Missing assessments and not evaluable designation
When no imaging/measurement is done at all at a particular time point, the subject is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
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assessment, the case is also considered NE at that time point, unless a convincing argument can 
be made that the contribution of the individual missing lesion(s) would not have changed the 
assigned time point response.
4.1.2
Confirmation of Scans and External Evaluation

Verification of Response: Confirmation of response (CR or PR) is required. Confirmed CR 
or PR will be claimed only if the criteria for each are met at a subsequent timepoint 
(minimum 4 weeks after criteria for an objective response are first met).

Verification of Progression: Progression of disease should be verified in cases where 
progression is equivocal. If repeat scans confirm PD, then progression should be declared 
using the date of the initial scan. If repeat scans do not confirm PD, then the subject is 
considered not to have progressive disease per RECIST 1.1.

External Evaluation of scans: For all subjects, BMS will request the transfer of anonymized 
scans for a BMS internal or external evaluation through a third party. For tumor types where 
data from study CA209-032 will potentially be used for future NDA submissions, BMS will 
request the transfer of anonymized scans from all subjects with this tumor type for a BMS 
internal or external evaluation through a third party.
4.2
Best overall response: All timepoints
The best overall response is determined once all the data for the subject is known. It is defined as 
the best response designation, as determined by the investigator, recorded between the date of 
first treatment and the date of objectively documented progression per RECIST1.1 or the date of 
subsequent therapy, whichever occurs first. For subjects without documented progression or 
subsequent therapy, all available response designations will contribute to the BOR assessment. 
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.
Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point (minimum 4 weeks after criteria of objective response are first met). In 
this circumstance, the best overall response can be interpreted as in Table 3.
Table 3:
Best overall response when confirmation of CR and PR IS required.
Overall response
Overall response
BEST overall response
First time point
Subsequent time 
point
CR
CR
CR
CR
PR
SD, PD or PRa
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Table 3:
Best overall response when confirmation of CR and PR IS required.
Overall response
Overall response
BEST overall response
First time point
Subsequent time 
point
CR
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
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.
For purposes of this study, the minimum scan time from baseline for determination of SD will be 
6 weeks.
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).
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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).
4.3.3
Immune related Response Criteria
Immune related response criteria using unidimensional measurements may be used to describe 
tumor shrinkage following RECIST defined disease progression Appendix 3. The methodology 
is the same as described above for RECIST except:

New lesions do not automatically denote disease progression

The measurement of longest diameter of new measurable lesions are in included in the sum 
of the measurements of the original target lesions.
Best immune related responses, for subjects who have progression followed by tumor shrinkage 
are classified as irCR (disappearance of all lesions) or irPR (30% reduction from baseline).
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APPENDIX 4
DEFINITION OF PRIOR RESPONSE TO PLATINUM-BASED 
CHEMOTHERAPY IN SCLC
Platinum sensitive: Progression free interval 90 days after completion of any platinum-based 
chemotherapy.
Platinum resistant: Progression free interval < 90 days after completion of any platinum-based
chemotherapy.
Platinum refractory: Progression during platinum-based chemotherapy.
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APPENDIX 5
DEFINITION OF PRIOR RESPONSE TO PLATINUM-BASED 
CHEMOTHERAPY IN OVARIAN CANCER
Platinum-sensitive: Relapse > 6 months after stop of any platinum-based chemotherapy.
Platinum-resistant: Relapse > 1 to 6 months after stop of any platinum-based chemotherapy.
Platinum-refractory: Relapse on or within 1 month after stop of any platinum-based 
chemotherapy.
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APPENDIX 6
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP

Premenarchal

Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female

A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 
45 years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level 
> 40 mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. 

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/mL at any time during the washout period, the woman can be considered 
postmenopausal.
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CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD 
BEARING POTENTIAL
One of the highly effective methods of contraception listed below is required during study 
duration and until the end of relevant systemic exposure, defined as 5 months after the end of 
study treatment in the female participant.
Local laws and regulations may require use of alternative and/or additional contraception 
methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 

oral 

intravaginal 

transdermal 

Progestogen-only hormonal contraception associated with inhibition of ovulationb 

oral 

injectable 
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b

Intrauterine device (IUD)c

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 

Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.

It is not necessary to use any other method of contraception when complete abstinence is 
elected. 

WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in the protocol. 

Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
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NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical 
studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method. Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative 
methods of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.

Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.

Male participants are required to use a condom for study duration and until the end of 
relevant systemic exposure, defined as 7 months after the end of treatment in the male 
participant.

Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end 
of treatment in the male participant.

Male participants with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile vaginal intercourse or use a male condom during each episode of penile 
penetration during the treatment and until 7 months after the end of treatment. 

Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of treatment.
Local laws and regulations may require use of alternative and/or additional contraception 
methods.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 6.4 and Section 6.1.1 on Serious Adverse Event 
Collection and Reporting.
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