Phase II Study of Nivolumab in Combination With Ipilimumab for Uveal Melanoma
Phase: PHASE2
Conditions: Metastatic Uveal Melanoma, Stage IV Uveal Melanoma AJCC v7
Sponsor: M.D. Anderson Cancer Center

 
 
1 
BMS Protocol #: 
CA184-187 
 
Local Protocol #:  
2011-0919 
 
Protocol Version/Date:  
Version 13:  08 October 2018 
 
 
TITLE:  Phase II Study of Nivolumab in combination with Ipilimumab for Uveal 
Melanoma 
 
Coordinating Center:  
The University of Texas MD Anderson Cancer Center 
 
 
Principal Investigator: 
Sapna P. Patel, MD 
 
 
 
 
1515 Holcombe Blvd Unit 0430 
 
 
 
 
Houston, TX 77030 
 
 
 
 
Telephone: 713-792-2921 
 
 
 
 
Fax: 713-745-1046 
sppatel@mdanderson.org 
 
Statistician: 
 
 
Roland L. Bassett, Jr., MS 
 
 
 
 
1515 Holcombe Blvd Unit 1411 
 
 
 
 
Houston, TX 77030 
 
 
 
 
Telephone: 713-563-4272 
rlbassett@mdanderson.org 
 
Study Coordinator: 
 
Suzanne Cain, BSN, RN, OCN 
 
 
 
 
 
1515 Holcombe Blvd Unit 0430 
 
 
 
 
 
Houston, TX 77030 
 
 
 
 
Telephone: 713-792-8874 
 
 
 
 
Fax: 713-745-1046 
 
 
 
 
scain@mdanderson.org 
 
 
Research Nurse: 
 
Michael Shephard, RN 
 
 
 
 
1515 Holcombe Blvd Unit 0430 
 
 
 
 
Houston, TX 77030 
 
 
 
 
Telephone: 713-745-1674 
 
 
 
 
Fax: 713-745-1046 
 
 
 
 
MPShephard@mdanderson.org 
 
Data Manager: 
 
Liberty Posada 
1515 Holcombe Blvd Unit 0430 
 
 
 
 
Houston, TX 77030 
 
 
 
 
Telephone: 713-792-2923 
 
 
 
 
Fax: 713-745-1046 
 
 
 
 
lposada@mdanderson.org 

 
 
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DOCUMENT HISTORY 
Summary of Changes 
 
SECTION 
SUMMARY OF CHANGE 
 
Cover Page 
Updated Version/Date 
 Exclusion Criteria p.  48 
Updated exclusion criteria to state concomitant palliative 
radiation for the purposes of symptom management is 
allowed.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
3 
TABLE OF CONTENTS .................................................................... 3 
PROTOCOL SYNOPSIS ................................................................... 8 
1 
INTRODUCTION ............................................................... 13 
1.1 
Research Hypothesis ...................................................... 13 
1.2 
Product Development Rationale .................................... 13 
1.2.1 
CTLA-4 and T Cell Activation ......................................................... 13 
1.3 
Summary of Results of Investigational Program .......... 17 
1.3.1 
Pharmacology of Ipilimumab ......................................................... 17 
1.3.2 
Animal Toxicology of Ipilimumab .................................................. 17 
1.3.3 
Clinical Pharmacology .................................................................... 19 
1.3.4 Mechanism of Action............................................................................... 19 
1.3.5 Pharmacokinetics .................................................................................... 20 
1.3.6 
Clinical Safety .................................................................................. 21 
1.3.7 
Clinical Efficacy: Melanoma Program............................................ 24 
1.3.7.a 
Rationale for Using Immune-Related Tumor Assessment 
Criteria (irRC) ................................................................................... 26 
1.3.7.b 
MDX010-20 (Phase 3, 3 mg/kg, previously treated 
melanoma) ....................................................................................... 26 
1.3.7.c 
CA184024 (Phase 3, previously untreated melanoma, 10 
mg/kg)............................................................................................... 28 
1.3.7.d 
10 mg/kg Dosing with Ipilimumab .................................................. 31 
1.3.7.e 
Advanced Melanoma ....................................................................... 32 
1.3.7.f 
Rationale for combining Nivolumab with 
ipilimumab…………………………………………………….................34 
1.3.7.g 
Rationale for Permitting Continued Treatment in Select  
Cases of Progressive 
Disease………………………………………........................................37 
1.4 
Overall Risk/Benefit Assessment .................................. 37 
1.5 
Uveal Melanoma .............................................................. 38 
1.6 
Study Rationale ............................................................... 39 
2 
STUDY OBJECTIVES ...................................................... 40 

 
 
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2.1 
Primary Objective ............................................................ 40 
2.2 
Secondary Objectives ..................................................... 40 
2.3  
Exploratory Objectives…………………………………….40 
3 
STUDY DESIGN ............................................................... 40 
3.1 
Screening and registration ............................................. 40 
3.2 
Study Schema ................................................................. 40 
3.3 
Treatment ......................................................................... 42 
3.3.1.a 
Induction Phase ............................................................................... 42 
3.3.1.b 
Maintenance Phase ......................................................................... 42 
3.3.1.c 
General Treatment Instructions ..................................................... 43 
3.4 
Follow-up (duration of study) ......................................... 43 
4 
SUBJECT SELECTION CRITERIA .................................. 44 
4.1 
Inclusion Criteria ............................................................. 44 
4.2 
Exclusion Criteria ............................................................ 47 
4.3 
Data Safety Monitoring Plan ........................................... 48 
5 
STUDY THERAPY ............................................................ 49 
5.1 
Nivolumab (BMS 936558) ................................................ 49 
5.2 
Ipilimumab ....................................................................... 49 
5.2.1 
Dose Calculations ........................................................................... 50 
5.2.2 
Dose Delay Criteria ......................................................................... 51 
5.2.3 
Discontinuation of Study Therapy ................................................. 52 
5.2.4 
Permanent Discontinuation of Ipilimumab .................................... 53 
5.2.4.a 
Permanent Discontinuation for Related Adverse Events ............ 53 
5.2.4.b 
Exceptions to Permanent Discontinuation ................................... 54 
5.2.5 
Immune-Related Adverse Events (irAEs)Reactions and 
Immune-mediated Adverse Reactions: Definition, 
Monitoring, and Treatment ............................................................. 56 
5.2.6 
Other Guidance ............................................................................... 56 
5.2.6.a 
Treatment of Nivolumab or  Ipilimumab-Related Isolated 
Drug Fever ....................................................................................... 58 

 
 
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5.2.6.b 
Monitoring and Management of Immune-mediated Adverse 
Reactions ......................................................................................... 57 
5.2.6.c 
Liver Function Test (LFT) Assessments Required Before 
Administration of Nivolumab or Ipilimumab ................................. 58 
5.3 
Prohibited and Restricted Therapies During the 
Study ................................................................................ 59 
5.3.1 
Prohibited Therapies ....................................................................... 59 
5.3.2 
Restricted Therapies ....................................................................... 58 
5.3.3 
Precautions ...................................................................................... 58 
6 
STUDY PROCEDURES AND OBSERVATIONS .............. 59 
6.1 
Time and Events Schedule ............................................. 60 
6.2 
Procedures by Visit ......................................................... 62 
6.2.1 
Study Procedures by Visit and Treatment Cycle .......................... 62 
6.2.1.a 
Screening/Baseline Visit ................................................................. 62 
6.2.1.b 
Treatment Visits .............................................................................. 62 
6.2.2  
Tissue Biopsies for Immune Biomarker Studies………………63 
6.2.3  
Exploratory Correlative Studies……………………………………63 
6.2.4 
Study Completion or Early Discontinuation Visit ......................... 63 
6.2.5 
Study Drug Discontinuation ........................................................... 63 
6.3 
Details of Procedures ..................................................... 63 
6.3.1 
Study Materials ................................................................................ 63 
6.3.2 
Safety Assessments ....................................................................... 63 
6.4 
Criteria for Evaluation ..................................................... 64 
6.4.1 
Safety Evaluation ............................................................................ 64 
6.4.2 
Efficacy Evaluation ......................................................................... 64 
6.4.2.a 
Definition of Measurable and Non-Measurable Lesions .............. 64 
6.4.2.b 
Definition of Index/Non-Index Lesions .......................................... 64 
6.4.3 
Definition of Tumor Response Using irRC .................................... 65 
6.4.3.a 
Definition of Index Lesions Response Using irRC ....................... 65 
6.4.3.b 
Definition of Non-Index Lesions Response Using irRC ............... 65 
6.4.3.c 
Impact of New Lesions on irRC ...................................................... 66 

 
 
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6.4.3.d 
Definition of Overall Response Using irRC ................................... 66 
6.4.3.e 
Immune-Related Best Overall Response Using irRC 
(irBOR).............................................................................................. 67 
6.4.4 
Response Endpoints ....................................................................... 68 
7 
INVESTIGATIONAL PRODUCT ....................................... 68 
7.1 
Identification .................................................................... 68 
7.2 
Packaging and Labeling ................................................. 69 
7.3 
Storage, Handling, and Dispensing ............................... 69 
7.3.1 
Storage ............................................................................................. 69 
7.3.2 
Handling and Disposal .................................................................... 70 
7.3.3 
Dispensing ....................................................................................... 70 
7.4 
Drug Ordering and Accountability ................................. 70 
7.4.1 
Initial Orders .................................................................................... 70 
7.4.2 
Re-Supply ......................................................................................... 71 
7.5 
Investigational Product Accountability ......................... 71 
7.6 
Investigational Product Destruction .............................. 71 
8 
ADVERSE EVENT REPORTING ...................................... 72 
8.1 
Collection of Safety Information .................................... 72 
8.1.1 
Definition of Serious Adverse Events............................................ 72 
8.1.2 
Definition of Nonserious Adverse Event ....................................... 73 
8.2 
Assignment of Adverse Event Intensity and 
Relationship to Investigational Product ........................ 73 
8.3 
Collection and Reporting ................................................ 74 
8.3.1 
Serious Adverse Events ................................................................. 74 
8.3.2 
Reporting to FDA ............................................................................. 77 
8.3.3 
Handling of Expedited Safety Reports .......................................... 77 
8.3.4 
Nonserious Adverse Events ........................................................... 77 
8.3.5 
Pregnancy ........................................................................................ 77 
8.3.6 
Other Safety Considerations .......................................................... 79 
9 
STATISTICAL METHODOLOGY ...................................... 79 

 
 
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9.1 
Efficacy Analysis ............................................................. 82 
9.2 
Secondary Analysis ........................................................ 82 
10 
ADMINISTRATIVE SECTION ........................................... 82 
10.1 
Compliance with the Protocol and Protocol 
Revisions ......................................................................... 82 
10.2 
Informed Consent ........................................................... 83 
10.3 
Records and Reports ...................................................... 83 
10.4 
Good Clinical Practice .................................................... 83 
10.5 
Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) ....................................................... 84 
10.6 
Records Retention .......................................................... 84 
APPENDIX A – MANAGEMENT ALGORITHMS ............................ 86 
LIST OF ABBREVIATIONS ............................................................ 94 
REFERENCES ................................................................................ 95 
 
 

 
 
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PROTOCOL SYNOPSIS 
 
Protocol Title: 
Nivolumab in combination with Ipilimumab for uveal 
melanoma 
Site Numbers & Names: 
The University of Texas MD Anderson Cancer Center 
Research Hypothesis: 
Among patients with metastatic uveal melanoma, treatment 
with nivolumab plus ipilimumab will demonstrate safety, 
tolerability, and efficacy in improving overall response  
Study Schema: 
Drugs / Doses / 
Length of Treatment) 
Metastatic uveal melanoma patients with at least one 
measureable lesion will be treated with nivolumab plus 
ipilimumab until disease progression or until 
unmanageable toxicity occurs. 
The doses used will be nivolumab 1 mg/kg and ipilimumab 
3 mg/kg, both intravenous (IV). 
During the induction phase, patients will be treated with 
nivolumab 1 mg/kg IV plus ipilimumab 3 mg/kg IV every 
3 weeks (+/- 7 days) for a total of four doses (week 1, 4, 7, 
10).  Treatment then continues at week 13 in the 
maintenance phase with nivolumab 480 mg IV every 4 
weeks until disease progression or unacceptable toxicity.  
Study Objectives: 
Primary: 
Secondary: 
Exploratory: 
PRIMARY OBJECTIVE: 
Overall response rate  
SECONDARY OBJECTIVES: 
Progression-free survival, median overall survival, one-
year overall survival 
EXPLORATORY OBJECTIVES: 
Exploratory objectives include tissue and blood correlates 
to define immune infiltration and signatures as a result of 
treatment with nivolumab plus ipilimumab.  
 
Study Design: 
Phase II study of nivolumab plus ipilimumab for metastatic 
uveal melanoma.   

 
 
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Accrual Goal: 
(Total number of patients) 
Metastatic uveal melanoma: Up to 39 patients to achieve 27 
evaluable patients 
 
Accrual Rate: 
(Number of patients 
expected per month) 
2-4 patients per month  
FPFV: 
LPFV: 
Follow Up: 
(dd-mmm-yy) 
01-Aug-2014 
05-Jan-2018  
Until death or alternate treatment 

 
 
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Inclusion Criteria: 
1. Willing and able to give written informed consent. 
2. History of uveal melanoma and documented metastatic disease 
with at least one measurable lesion is required, which is > 1 cm x 
1 cm (on spiral CT or equivalent).  
3. Any number of prior therapies is allowed. 
4. Required values for initial laboratory tests: WBC  2000/uL, 
ANC  1000/uL, Platelets  100 x 103/uL, Hemoglobin  9 
g/dL, Creatinine  1.5 x ULN, or creatinine clearance (CrCl > 
40mL/min (using the Cockcroft-Gault formula) AST/ALT  3 x 
ULN for patients without liver metastasis,  5 x ULN for liver 
metastases, Bilirubin  1.5 x ULN, (except patients with 
Gilbert’s Syndrome, who must have a total bilirubin less than 3.0 
mg/dL) 
5. In suspected patients, no active or chronic infection with HIV, 
Hepatitis B, or Hepatitis C. 
6. Performance status ECOG 0-1.  
7. Men and women  18 years of age.  
8. Baseline imaging in the form of CT chest, abdomen, pelvis with 
oral and intravenous contrast within 28 days of study entry.  For 
patients with a contrast allergy, choice of alternative body 
imaging will be at the discretion of the investigator or his 
designee.  MRI of the brain is only needed if clinically indicated. 
9. More than 21 days elapsed from surgery, radiation therapy, or 
prior chemotherapy.  More than 42 days elapsed from prior 
immune therapy including vaccines.   
10. Women of childbearing potential (WOCBP) and fertile men with 
partners of childbearing potential must be using an adequate 
method of contraception to avoid pregnancy throughout the study 
and for up to 26 weeks after the last dose of investigational 
product, in such a manner that the risk of pregnancy is minimized.  
 

 
 
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Exclusion Criteria: 
1. Untreated primary uveal melanoma except in cases where 
metastatic disease is diagnosed at the time of primary disease.   
2. Metastatic uveal melanoma patients with bone-only disease.  
3. Any other malignancy from which the patient has been disease-free 
for less than 2 years, with the exception of adequately treated and 
cured basal or squamous cell skin cancer, superficial bladder cancer 
or carcinoma in situ of the cervix, breast, or prostate.  
4. Autoimmune disease: Patients with a history of inflammatory bowel 
disease, including ulcerative colitis and Crohn’s Disease, are 
excluded from this study, as are patients with a history of 
symptomatic 
disease 
(e.g., 
rheumatoid 
arthritis, 
systemic 
progressive sclerosis [scleroderma], systemic lupus erythematosus, 
autoimmune vasculitis [e.g., Wegener’s Granulomatosis]); motor 
neuropathy considered of autoimmune origin (e.g. Guillain-Barre 
Syndrome and Myasthenia Gravis). 
5. Any underlying medical or psychiatric condition, which in the 
opinion of the investigator will make the administration of 
ipilimumab hazardous or obscure the interpretation of AEs, such as 
a condition associated with frequent diarrhea. 
6. Any non-oncology vaccine therapy used for prevention of infectious 
diseases for up to 1 month before or after any dose of ipilimumab. 
7. Concomitant therapy with any of the following: tamoxifen, 
toremifene, IL-2, interferon, or other non-study immunotherapy 
regimens; cytotoxic chemotherapy; immunosuppressive agents; 
other investigation therapies; or chronic use of systemic 
corticosteroids greater than physiologic replacement doses. Ocular 
steroid use is acceptable. 
8. Women of childbearing potential (WOCBP), defined above in 
Section 4.1, who: 
a. 
are unwilling or unable to use an acceptable method of 
contraception to avoid pregnancy for their entire study 
period and for up to 26 weeks after cessation of study drug, 
or 
b. have a positive pregnancy test at baseline, or 
c. 
are pregnant or breastfeeding. 
9. Prisoners or subjects who are compulsorily detained (involuntarily 
incarcerated) for treatment of either a psychiatric or physical (e.g., 
infectious) illness. 

 
 
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Criteria for Evaluation: 
(Efficacy, safety, 
stopping rules, etc.) 
Efficacy will be evaluated at week 12 and then every 12 
weeks until progression or treatment discontinuation.   
Safety will be assessed at every treatment visit. 
Statistics: 
A single-stage trial design will be employed.   
 Type I error rate of 5%, power of 80% 
 Null hypothesis of 5% response rate 
 Alternate hypothesis of 20% response rate 
 Response will be defined as those patients who 
achieve RECIST CR + PR.   
 Accounting for attrition (inevaluable patients, 25%) 
and screen fails (5%), up to 39 patients are needed to 
achieve a target enrollment of 27 evaluable patients. 
 

 
 
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1.  INTRODUCTION 
1.1 RESEARCH HYPOTHESIS 
Among patients with metastatic uveal melanoma, treatment with nivolumab plus 
ipilimumab will demonstrate safety, tolerability, and efficacy in improving response rate 
compared with ipilimumab alone. 
1.2 Product Development Rationale 
1.2.1 CTLA-4 and T Cell Activation 
Figure 1 
Mechanism of Action 
 
Advances in the understanding of the mechanisms that regulate T cell activation have 
allowed the rational design of new strategies for immunotherapy of tumors, including 
melanoma. It has been known for some time that engagement of the T cell antigen receptor 
by itself is not sufficient for full T cell activation; a second co-stimulatory signal is required 
for induction of IL-2 production, proliferation and differentiation to effector function of 
naive T cells. Abundant data now indicate that the primary source of this costimulation is 
mediated by engagement of CD28 on the T cell surface by members of the B7 family on 
the antigen-presenting cell (APC).1 (Figure 1.) 
Expression of B7 has been shown to be limited to “professional” antigen presenting cells; 
that is, specialized cells of the hematopoietic lineage, including dendritic cells, activated 
macrophages, and activated B cells. It has been suggested that this sharply-defined 
restriction of B7 expression is a fail-safe mechanism for maintenance of peripheral T cell 
tolerance, insuring that T cell activation can only be stimulated by appropriate APCs.2 The 

 
 
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fact that tumor cells do not express B7 contributes to their poor capacity to elicit immune 
responses.3,4 
The demonstration that induction of expression of B7 on many tumor cells by transfection, 
transduction, or other mechanisms can heighten tumor immunogenicity led to great interest 
in pursuing this as an approach to tumor immunotherapy. As demonstrated in vivo in 
murine tumor models, the utility of B7 expression as a vaccination approach is limited by 
the following factors: (1) B7-expressing tumor cell vaccines are only effective when the 
tumor cells have a high degree of inherent immunogenicity; (2) while B7-expressing 
vaccines have been shown in many cases to be effective in inducing protective immune 
responses, they have demonstrated only limited utility in inducing responses to established 
tumors; and (3) inactivation of tumor cells by radiation has been shown to destroy the 
immuno-enhancing activity of the B7 gene product.5,6  
In the past few years it has become apparent that co-stimulation is even more complex than 
originally thought. After activation, T cells express CTLA-4, a close homologue to CD28. 
CTLA-4 binds members of the B7 family with a much higher affinity than 
CD28.7Although there was initially some controversy as to the role of CTLA-4 in 
regulating T cell activation, it has become clear that CTLA-4 down-regulates T cell 
responses.8  
  
This was initially suggested by the following in vitro observations: (1) blockade of CTLA-
4/B7 interactions with antibody enhanced T cell responses; (2) cross-linking of CTLA-4 
with CD3 and CD28 inhibited T cell responses; and (3) administration of antibodies to 
CTLA-4 in vivo enhanced the immune response to peptide antigens or superantigens in 
mice.9,10,11,12 Blocking CTLA-4-B7 interaction while preserving signaling via CD28 
resulted in enhanced T cell responses in vitro.10 
Perhaps the most convincing demonstration of the down-regulatory role of CTLA-4 came 
from examination of mice with a null mutation.13,14,15 CTLA-4 knockout mice appear to 
have spontaneously activated T cells evident at approximately 1 week after birth, followed 
by rampant lymphoproliferation and lymphadenopathy. These mice die at approximately 3 
weeks of age, either as a result of polyclonal T cell expansion and tissue destruction or as 
a result of toxic shock resulting from lymphokine production by the T cells. Since 
thymocyte differentiation and selection proceed normally in CTLA-4-deficient mice, the 
rampant T cell expansion that occurs in the mice indicates that CTLA-4 plays a critical role 
in down-regulating T cell responses in the periphery.12 

 
 
15 
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather 
than as self and can be effectively attacked by an activated immune system. An effective 
immune response in this setting is thought to rely on immune surveillance of tumor 
antigens expressed on cancer cells that ultimately results in an adaptive immune response 
and cancer cell death. This functions by aborting the emergence of tumors as they arise 
and/or causing tumor shrinkage where it is present. Meanwhile, tumor progression may 
depend upon acquisition of traits that allow cancer cells to evade immune surveillance and 
an effective immune response. This evasion may occur by exploiting any of the 
checkpoints that control the regulatory immune response, including display of antigens and 
control of co-stimulatory pathways that affect the proliferation of cells involved in 
immunity. Current immunotherapy efforts attempt to break the apparent tolerance of the 
immune system to tumor cells and antigens by either introducing cancer antigens by 
therapeutic vaccination or by modulating regulatory checkpoints of the immune system - 
either directly by stimulation of immune cells by antibodies directed to receptors on T and 
B cells or indirectly by cytokine manipulation. T-cell stimulation is a complex process 
involving the integration of numerous positive, as well as negative, costimulatory signals 
in addition to antigen recognition by the T-cell receptor (TCR).2 Collectively, these signals 
govern the balance between T-cell activation and tolerance to antigens.1 
 
Programmed death receptor-1 (PD-1, CD279), a 55 kD type I transmembrane protein, is a 
member of the CD28 family of T-cell costimulary receptors that also includes CD28, 
CTLA-4, ICOS, and BTLA.2 PD-1 contains an intracellular membrane proximal 
immunoreceptor tyrosine inhibitory motif (ITIM) and a membrane distal immunoreceptor 
tyrosine-based switch motif (ITSM). Two ligands specific for PD-1 have been identified: 
PD-L1 (B7-H1/CD274) and PD-L2 (B7-DC/CD273). PD-L1 and PD-L2 have been shown 
to down-regulate T-cell activation upon binding to PD-1 in both murine and human 
systems.3,4 PD-1 delivers a negative signal by the recruitment of a protein tyrosine 
phosphatase SHP-2 to the phosphorylated tyrosine residue in the ITSM in its cytoplasmic 
region.5,6 PD-1 is primarily expressed on activated T cells, B cells and myeloid cells.7 
 
Further evidence for a negative regulatory role of PD-1 comes from studies of PD-1-
deficient mice. PD-1-deficient mice develop various autoimmune phenotypes, including 
dilated cardiomyopathy, a lupus-like syndrome with arthritis and nephritis, and accelerated 
diabetes mellitus.8,9,10  The emergence of these autoimmune phenotypes is dependent 
upon the genetic background of the mouse strain and many of these phenotypes emerge at 

 
 
16 
different times and show variable penetrance. In addition to the phenotypes of null 
mutations, PD-1 inhibition by antibody-mediated blockade in several murine models has 
been found to play a role in the development of autoimmune diseases such as 
encephalomyelitis, graft-versus-host disease, and type I diabetes.11,12 Taken together, 
these results suggest that PD-1 blockade has the potential to activate anti-self T-cell 
responses, but these responses are variable and dependent upon various host genetic 
factors. Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of 
tolerance to self antigens. 
 
Preclinical animal models of tumors have shown that blockade by PD-1 by monoclonal 
antibodies (mAbs) can enhance the anti-tumor immune response and result in tumor 
rejection.  Antitumor activity by PD-1 blockade functions in PD-L1+ tumors as well as in 
tumors that are negative for the expression of PD-L1.13,14,15,16,17,18 This suggests that 
host mechanisms (ie, expression of PD-L1 in antigen-presenting cells) limit the antitumor 
response. Consequently, both PD-L1 positive and negative tumors may be targeted using 
this approach. In humans, constitutive PD-L1 expression is normally limited to 
macrophage-lineage cells, although expression of PD-L1 can be induced on other 
hematologic cells as well, including activated T cells. However, aberrant expression of PD-
L1 
by 
tumor 
cells 
has 
been 
reported 
in 
a 
number 
of 
human 
malignancies.19,20,21,22,23,24,25 PD-L1 expressed by tumor cells has been shown to 
enhance apoptosis of activated tumor-specific T cells in vitro.7 Moreover, the expression 
of PD-L1 may protect the tumor cells from the induction of apoptosis by effector T cells.26  
Retrospective analyses of several human tumor types suggest that tumor over-expression 
(as measured by IHC) of PD-L1 may permit immune evasion by tumors. In renal cell 
carcinoma, high surface expression levels of PD-L1 on tumor cells are related to tumor 
aggressiveness.20,24  Subjects with high tumor and/or lymphocyte PD-L1 levels are 4.5 
times more likely to die from their cancer than subjects exhibiting low levels of PD-L1 
expression. In addition, in multivariate analysis, high expression of PD-L1 is correlated to 
have a worse overall survival rate compared to low expression levels of PD-L1.27 
 
Nivolumab is a fully human, IgG4 (kappa) isotype, mAb that binds PD-1. Blockade of the 
PD-1 pathway by nivolumab was studied using the mixed lymphocyte reaction (MLR). 
PD-1 blockade resulted in a reproducible enhancement of both proliferation and IFN-α 
release in the MLR.28  The effect of nivolumab on antigen-specific recall response was 
investigated using a CMV-restimulation assay with human peripheral blood mononuclear 

 
 
17 
cells (PBMCs), and was evaluated by ELISA. 
 
These data indicated that nivolumab, versus an isotype-matched control antibody, 
augmented IFN-α secretion from CMV-specific memory T-cells in a dose-dependent 
manner. PD-1 blockade by nivolumab is therefore considered a promising 
immunotherapeutic option. 
 
1.3 Summary of Results of Investigational Program 
1.3.1 Pharmacology of Ipilimumab 
Ipilimumab is a human immunoglobulin G (IgG1)κ anti-CTLA-4 monoclonal antibody 
(mAb). In vitro studies were performed with ipilimumab to demonstrate that it is specific 
for CTLA-4, actively inhibits CTLA-4 interactions with B7.1 and B7.2, does not show any 
cross-reactivity with human B7.1, B7.2 negative cell lines, and stains the appropriate cells 
without non-specific cross-reactivity in normal human tissues, as demonstrated by 
immunohistochemistry. Ipilimumab does cross-react with CTLA-4 in non-human primates 
including cynomolgus monkeys. 
1.3.2 Animal Toxicology of Ipilimumab 
The effects of ipilimumab on prenatal and postnatal development in monkeys have not 
been fully investigated. Preliminary results are available from an ongoing study in 
cynomolgus monkeys. Pregnant monkeys received ipilimumab every 21 days from the 
onset of organogenesis in the first trimester through delivery, at dose levels either 2.6 or 
7.2 times higher than the clinical dose of 3 mg/kg of ipilimumab (by AUC). No treatment-
related adverse effects on reproduction were detected during the first two trimesters of 
pregnancy. Beginning in the third trimester, the ipilimumab groups experienced higher 
incidences of abortion, stillbirth, premature delivery (with corresponding lower birth 
weight), and higher incidences of infant mortality in a dose-related manner compared to 
controls. 
Genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/-), the target for 
ipilimumab, appeared healthy and gave birth to healthy CTLA-4+/- heterozygous 
offspring. Mated CTLA-4+/- heterozygous mice also produced offspring deficient in 
CTLA-4 (homozygous negative, CTLA-4-/-). The CTLA-4-/- homozygous negative 
offspring appeared healthy at birth, exhibited signs of multiorgan lymphoproliferative 

 
 
18 
disease by 2 weeks of age, and all died by 3–4 weeks of age with massive 
lymphoproliferation and multiorgan tissue destruction. 
Complete information on the pre-clinical toxicology studies can be found in the 
Ipilimumab Investigator Brochure (IB). Non-clinical toxicity assessments included in vitro 
evaluation for the potential of ipilimumab to mediate complement-dependent cellular 
cytotoxicity (CDCC) or antibody-dependent cellular cytotoxicity (ADCC), and toxicology 
assessments in cynomolgus monkeys alone and in the presence of vaccines. 
The in vitro studies demonstrated that ipilimumab did not mediate CDCC of PHA- or 
(CD)3-activated human T cells. However, low to moderate ADCC activity was noted at 
concentrations up to 50 ug/mL. These data are consistent with the requirement of high 
levels of antigen expression on the surface of target cells for efficient ADCC or CDCC. 
Since ipilimumab is a human IgG1, an isotype generally capable of mediating CDCC and 
ADCC, the lack of these activities is likely due to a very low expression of CTLA-4 on 
activated T cells. Therefore, these data suggest that ipilimumab treatment would not result 
in depletion of activated T cells in vivo. Indeed, no depletion of T cells or T cell subsets 
were noted in toxicology studies in cynomolgus monkeys. 
No mortality or signs of toxicity were observed in three independent 14-day intravenous 
toxicology studies in cynomolgus monkeys at multiple doses up to 30 mg/kg/dose. 
Furthermore, ipilimumab was evaluated in sub-chronic and chronic toxicology studies in 
cynomolgus monkeys with and without Hepatitis B (HepB) Vaccine and Melanoma 
Vaccine. Ipilimumab was well tolerated alone or in combination in all studies. There were 
no significant changes in clinical signs, body weight values, clinical pathology values or T 
cell activation markers. In addition, there were no significant histopathology changes in 
the stomach or colon. 
 
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-α 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 

 
 
19 
effector cells and decreased intratumoral T regulatory cells, as compared to either agent 
alone. 
Preclinically, 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. 
 
1.3.3 Clinical Pharmacology 
1.3.4 Mechanism of Action 
CTLA-4 is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and 
blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has 
been shown to augment T-cell activation and proliferation. The mechanism of action of 
ipilimumab’s effect in patients with melanoma is indirect, possibly through T-cell mediated 
anti-tumor immune responses. 
Nivolumab is a fully human, IgG4 (kappa) isotype, mAb that binds PD-1. Blockade of the 
PD-1 pathway by nivolumab was studied using the mixed lymphocyte reaction (MLR). 
PD-1 blockade resulted in a reproducible enhancement of both proliferation and IFN-α 
release in the MLR.28  The effect of nivolumab augmented IFN-α secretion from CMV-
specific memory T-cells in a dose-dependent manner. PD-1 blockade by nivolumab is 
therefore considered a promising immunotherapeutic option. 
 

 
 
20 
1.3.5 Pharmacokinetics 
Ipilimumab Monotherapy 
Ipilimumab has a terminal half life of approximately 15.4 days. The expected in vivo 
degradation of monoclonal antibodies is to small peptides and amino acids via biochemical 
pathways that are independent of cytochrome P450 enzymes.  
The population PK of ipilimumab was studied with 785 subjects and demonstrated that PK 
of ipilimumab is linear and exposures are dose proportional across the tested dose range of 
0.3 to 10 mg/kg, and the model parameters are time invariant. Upon repeated dosing of 
ipilimumab, administered every three weeks, minimal systemic accumulation was 
observed by an accumulation index of 1.5-fold or less and ipilimumab steady-state 
concentrations were achieved by the third dose. The ipilimumab clearance of 16.8 mL/h 
from population PK analysis is consistent with that determined by PK analysis. The 
terminal half-life (T-HALF) and Vss of ipilimumab calculated from the model were 15.4 
days, and 7.47 L, which are consistent with that determined by non-compartmental analysis 
(NCA). Volume of central (Vc) and peripheral compartment were found to be 4.35 L and 
3.28 L, respectively, suggesting that ipilimumab first distributes into plasma volume and 
subsequently into extracellular fluid space. Clearance of ipilimumab and Vc were found to 
increase with increase in body weight. Nevertheless, there was no significant increase in 
exposure with increase in body weight when dosed on a mg/kg basis, supporting dosing of 
ipilimumab based on a weight normalized regimen. Additional details are provided in 
investigator brochure. 
Nivolumab Monotherapy 
Single-dose pharmacokinetics (PK) of nivolumab was evaluated in subjects with multiple 
tumor types in MD1106-01 whereas multiple dose PK is evaluated in subjects in 
CA209003. In addition, a preliminary population pharmacokinetic (PPK) model has been 
developed with data from 
 350 subjects from MDX1106-01, MDX1106-02 and 
CA209003.  
Single-dose PK of nivolumab was evaluated in 39 subjects with multiple tumor types in 
study MDX1106-01 in the dose range of 0.3 to 10 mg/kg. The median Tmax across single 
doses ranged from 1.6 to 3 hours with individual values ranging from 0.9 to 7 hours. The 
PK of nivolumab is linear in the range of 0.3 to 10 mg/kg with dose proportional increase 
in Cmax and AUC(INF) with low to moderate inter-subject variability observed at each 
dose level (ie, CV ranging from 7 to 45%). Geometric mean clearance (CL) after a single 

 
 
21 
intravenous (IV) dose ranged from 0.13 to 0.19 mL/h/kg, while mean volume of 
distribution (Vz) varied between 83 to 113 mL/kg across doses. The mean terminal T-
HALF of nivolumab is 17 to 25 days, which is consistent with half life of endogenous 
IgG4, indicating that the elimination mechanism of nivolumab may be similar to IgG4. 
Both elimination and distribution of nivolumab appear to be independent of dose in the 
dose range studied. Additional details are provided in the Investigator Brochure. 
A preliminary PPK model was developed by nonlinear mixed effect modeling using data 
from 350 subjects from MDX1106-01, MDX1106-02 and CA209003. The body weight 
normalized dosing produces approximately constant trough concentrations over a wide 
range of body weight, and hence is appropriate for future clinical trials of nivolumab. 
Clearance of nivolumab is similar in all tumor types studied and is independent of dose 
range studied (0.1 to 10 mg/kg). 
 
1.3.6 Clinical Safety  
Ipilimumab Monotherapy 
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%), 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 
One study has contributed most to the clinical experience with nivolumab monotherapy in 
subjects with melanoma and other solid malignancies. CA209003 is an ongoing Phase 1 
open label, multiple dose escalation study in 304 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 03-Jul-2012, a total of 107 melanoma subjects were treated with nivolumab in the dose 

 
 
22 
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 72.4% of subjects. The most frequent nivolumab 
related AEs occurring in 5% of subjects included: fatigue (25.7%), rash (13.5%), diarrhea 
(11.8%), pruritis (10.2%), nausea (7.9%), decreased appetite (7.9%), hemoglobin 
decreased (5.9%) and pyrexia (5.3%).  The majority of events were low grade, with grade 
3-4 drug related AEs observed in 14.8% of subjects. The most common Grade 3-4 drug-
related AEs occurring in  1% of subjects were: fatigue (1.6%), lymphopenia (1.3%), 
abdominal pain (1%), diarrhea (1%), hypophosphatemia (1%) and pneumonitis (1%). At 
least one SAE was reported for 150 (49.3%) of the 304 subjects at all dose levels. Grade 
3-4 SAEs were reported for 23 subjects (7.6%). 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%). Additional select treatment-related AEs have occurred with 
low frequency (< 5%) but are considered clinically meaningful, as they require greater 
vigilance for early recognition and prompt intervention. These AEs include: ALT increased 
(4.3%), AST increased (3.6%), pneumonitis (3.3%), hypothyroidism (3.0%), 
hyperthyroidism (1.3%), renal failure (1.0%), adrenal insufficiency (0.7%) and colitis 
(0.7%). Grade 3-4 events of pneumonitis were reported in 3 subjects (1.0%) as described 
above (1 event was Grade 4). Grade 3 events of colitis, ALT increased, and AST increased 
were reported in 2 subjects (0.7%) each. Grade 3 events of adrenal insufficiency, 
hyperthyroidism, and hypothyroidism were reported in 1 subject (0.3%) each. Treatment-
related AEs leading to discontinuation were reported in 18 (5.9%) of the 304 treated 
subjects on CA209003. The only events reported in more than 1 subject were pneumonitis 
(4 subjects; 1.3%) and hepatitis (2 subjects; 0.7%). There were 3 (1%) drug related deaths; 
each occurred after development of pneumonitis. 
Preliminary new non-clinical safety findings of adverse pregnancy outcomes and infant 
losses in the absence of overt maternal toxicity have been reported.44 The findings of 
increased late stage pregnancy loss and early infant deaths/euthanasia in nivolumab 
exposed pregnant monkeys suggest a potential risk to human pregnancy if there is 
continued treatment with nivolumab during pregnancy.   
Additional details on the safety profile of nivolumab, including results from other clinical 
studies, are also available in the BMS-936558 (nivolumab) IB. 

 
 
23 
 
Nivolumab Combined with Ipilimumab 
In the Phase 1 study CA209004, ascending doses of nivolumab have been studied 
concomitantly with ascending doses of ipilimumab in subjects with unresectable or 
metastatic melanoma. In each arm 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 1.0 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-16).  The following DLTs were observed 
in Cohort 1 - Grade 3 elevated AST/ALT (1 subject); in Cohort 2 - Grade 3 uveitis (1 
subject) and Grade 3 elevated AST/ALT (1 subject) and in Cohort 3 - Grade 4 elevated 
lipase (2 subjects) and Grade 3 elevated lipase (1 subject). Based on these data, Cohort 2 
was identified as the maximum tolerated dose (MTD) and Cohort 3 exceeded the MTD. 
As of 15-Feb-2013, a total of 53 melanoma subjects were treated with nivolumab combined 
with ipilimumab in CA209004 across cohorts 1, 2, 2a, and 3. At least one AE regardless 
of causality has been reported in 98% of subjects treated. The most common (reported at > 
10% incidence) treatment related AEs (any Grade %; Grade 3-4 %: 93; 53) are rash (55; 
4), pruritus (47; 0), vitiligo (11; 0), fatigue (38; 0), pyrexia (21, 0), diarrhea (34; 6), nausea 
(21, 0), vomiting (11, 2), ALT increased (21; 11), AST increased (21; 13), lipase increased 
(19; 13), amylase increased (15, 6), headache (11, 0), and cough (13, 0). 
The majority of AEs leading to discontinuation (regardless of causality) were Grade 3 or 4 
(reported in 11 of 53 subjects, 21%). Grade 3 events included lipase increased, ALT 
increased, AST increased, troponin I increased, colitis, diverticular perforation, 
pancreatitis, tachycardia, renal failure acute, choroiditis, autoimmune disorder, and 
pneumonitis. One subject each discontinued due to Grade 4 events of blood creatinine 
increased and AST increased. No drug-related deaths were reported. 
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 renal toxicity. Prompt interventions are recommended 

 
 
24 
according to the management algorithms and in addition include ophthalmologic 
evaluations for any visual symptoms in order to evaluate for nivolumab or ipilimumab 
related uveitis. 
Given the nature of the study and in order to standardize the management of adverse events 
the recommendations are to follow the BMS-936558 (nivolumab) adverse event algorithms 
and not the ipilimumab IB algorithms. 
The algorithms recommended for utilization in CA209067 are contained in Appendix B. 
As of 03-Apr-2013, three subjects out of approximately 1200 patients on nivolumab 
clinical trials have developed opportunistic infections (2 cases of Aspergillus pneumonia, 
and 1 case of Pneumocystis jiroveci pneumonia) after receiving prolonged treatment with 
high dose steroids for nivolumab-related adverse events. Details of these cases are available 
in the Investigator Brochure. Because of the potential for opportunistic infections with 
prolonged high dose corticosteroids administration, the following recommendations should 
be considered for subjects with inflammatory events expected to require more than 4 weeks 
of corticosteroids or other immunosuppressants to manage the adverse event: 
 Antimicrobial/antifungal prophylaxis per institutional guidelines to prevent opportunistic 
infections such as Pneumocystis jiroveci and fungal infections. 
 Early consultation with an infectious disease specialist should be considered. Depending 
on the presentation, consultation with a pulmonologist for bronchoscopy or a 
gastroenterologist for endoscopy may also be appropriate. 
 In patients that develop recurrent adverse events in the setting of ongoing or prior 
immunosuppressant use, an opportunistic infection should be considered in the differential 
diagnosis. 
Additional details on the safety of nivolumab, including results from other clinical studies, 
are available in the IB. 
1.3.7 Clinical Efficacy: Melanoma Program 
Ipilimumab Monotherapy 
In melanoma, a completed Phase 3 study (MDX010-20) has demonstrated a clinically 
meaningful and statistically significant survival benefit in pre-treated advanced melanoma. 
The study compared the overall survival (OS) of ipilimumab plus a melanoma-specific 
vaccine (gp100) to that of gp100 alone. A second comparison defined the OS of ipilimumab 

 
 
25 
alone vs. gp100 alone. Both comparisons demonstrated statistically significant 
improvements in OS (p = 0.0004 and 0.0026, respectively). The 1-year survival for the two 
ipilimumab-containing groups, respectively, was 44% and 46% respectively, compared to 
25% for the gp100 control group. The 2-year survival was 22%, 24% and 14% respectively. 
The median survival was 10, 10.1, and 6.4 months, for ipilimumab plus gp100, ipilimumab 
monotherapy, and gp100 monotherapy, respectively. 
Nivolumab Monotherapy 
In CA209003, the clinical activity of nivolumab was demonstrated in a variety of tumor 
types, including melanoma, RCC, and NSCLC. Clinical activity was noted across a range 
of doses  (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg). 
In CA209003, as of the clinical cut-off date of 03-Jul-2012, a total of 304 subjects with 
melanoma, RCC, and NSCLC have been evaluated for clinical activity. A response of 
either CR or PR, as determined by investigator assessed tumor evaluations based on 
modified irRC, has been reported at all dose levels. No responses (CR or PR) have been 
reported in subjects with colorectal carcinoma or castrate-resistant prostate cancer. 
Among 106 patients with advanced melanoma who received nivolumab and were evaluable 
for response, the preliminary objective response rates were 6/17 (35%), 5/18 (28%), 11/34 
(32%), 7/17 (41%), and 4/20 (20%) for melanoma subjects treated at 0.1, 0.3, 1, 3, and 10 
mg/kg, respectively. Duration of response range from 3.6 to 11.2, 1.8 to 9.2, 1.9 to 24.9, 
9.2 to 22.4, and 17.0 to 25.7 months in the melanoma subjects treated at 0.1, 0.3, 1, 3, and 
10 mg/kg, respectively. Stable disease  24 weeks occurred in an additional 1/18 (6%), 
4/34 (12%), 1/17(6%) melanoma subjects at 0.3, 1, and 3 mg/kg, respectively. Finally, the 
PFS-24 week was 41%, 33%, 48%, 55%, and 30% in melanoma subjects treated at 0.1, 
0.3, 1, 3, and 10 mg/kg, respectively. 
Nivolumab Combined with Ipilimumab 
As of the 15-Feb-2013 clinical cut-off in CA209004, of the 52 subjects evaluable for 
response, 21 subjects (40%) had an objective response by modified World Health 
Organization (mWHO) criteria. In an additional 2 subjects (4%) there was an unconfirmed 
objective response. In Cohort 1 (0.1 mg/kg nivolumab + 3 mg/kg ipilimumab), 3 out of 14 
evaluable subjects had an objective response by mWHO (21%); 1 CR and 2 PRs with an 
additional PR by immune-related mWHO criteria (irPR). 55 In Cohort 2 (1 mg/kg 
nivolumab + 3 mg/kg ipilimumab), 9 out of 17 evaluable subjects had an objective response 
by mWHO (53%; 3 CRs (18%), 6 PRs (35%) with two additional subjects experiencing 
immune-related SD (irSD). In Cohort 2a (3 mg/kg nivolumab + 
1 mg/kg ipilimumab), 6 out of 15 response evaluable subjects had an objective response 
rate by mWHO (40%; 1 CR (7%), 5 PRs (33%) with 2 additional uPRs (13%) and 2 irSDs 
and 1 irPR).  In Cohort 3 (3 mg/kg nivolumab + 3 mg/kg ipilimumab), 3 out of 6 evaluable 
subjects had an objective response by mWHO (50%; 3 PRs (50%) with 1 additional irPR 
and 1 irSD. 
Preliminary analysis revealed 16 of the 52 evaluable subjects (31%) had > 80% reduction 
in the size of target tumor lesions by the week 12 evaluation. This is compared to < 2% for 

 
 
26 
3 mg/kg ipilimumab monotherapy based on CA184020 (N=540) and < 3% for nivolumab 
monotherapy based on CA209003 (N=94, 0.1-10 mg/kg). 
1.3.7.a Rationale for Using Immune-Related Tumor Assessment Criteria 
(irRC) 
Ipilimumab is an immuno-stimulating antibody with evidence of anti-cancer activity 
(durable objective response and stable disease) in subjects with advanced melanoma, 
including subjects with established brain disease. Observations of clinical activity defined 
by tumor response endpoints defined by conventional criteria (eg, mWHO) may be 
inadequate to realize the kinetics and magnitude of clinical benefit achieved with 
ipilimumab. 
Histopathologic evidence has demonstrated ipilimumab can produce an influx or expansion 
of tumor infiltrating lymphocytes. Therefore, early increases in lesion size detected 
radiologically or upon gross examination could be misinterpreted as progressive tumor 
growth and precede objective tumor shrinkage. In addition the appearance of new lesions 
may have categorized a subject to have progressive disease using conventional tumor 
assessment criteria despite the concurrent observation of objective tumor responses in pre-
existing lesions and a net reduction in global tumor burden that includes the new lesions. 
Hence the appearance of new lesions in and of themselves may not necessarily constitute 
progressive disease. The immune-related response criteria (irRC) were developed as a tool 
to gauge tumor response using the changes in global tumor burden. In addition, the irRC 
may be useful to inform a physician’s decision to continue dosing in subjects who may 
receive benefit from additional ipilimumab therapy. The ir-response assessment is based 
solely on objective measurements (SPD) of index and new lesions. Non-index lesions are 
not considered. 
1.3.7.b MDX010-20 (Phase 3, 3 mg/kg, previously treated melanoma) 
MDX010-20, a randomized (3:1:1), double-blind, double-dummy study included 
676 randomized subjects with unresectable or metastatic melanoma previously treated with 
one or more of the following: aldesleukin, dacarbazine, temozolomide, fotemustine, or 
carboplatin. Of these 676 subjects, 403 were randomized to receive ipilimumab at 3 mg/kg 
in combination with an investigational peptide vaccine with incomplete Freund’s adjuvant 
(gp100), 137 were randomized to receive ipilimumab at 3 mg/kg, and 136 were randomized 
to receive gp100 alone. The study enrolled only subjects with HLA A2*0201 genotype; 
this HLA genotype facilitates the immune presentation of the investigational peptide 
vaccine. The study excluded subjects with active autoimmune disease or those receiving 

 
 
27 
systemic immunosuppression for organ transplantation. Ipilimumab/placebo was 
administered at 3 mg/kg as an intravenous infusion every 3 weeks for 4 doses. 
Gp100/placebo was administered at a dose of 2 mg peptide by deep subcutaneous injection 
every 3 weeks for four doses. Assessment of tumor response was conducted at Weeks 12 
and 24, and every 3 months thereafter. Subjects with evidence of objective tumor response 
at 12 or 24 weeks had assessment for confirmation of durability of response at 16 or 28 
weeks, respectively. 
The major efficacy outcome measure was overall survival (OS) in the ipilimumab + gp100 
arm compared to that in the gp100 arm. Secondary efficacy outcome measures were OS in 
the ipilimumab + gp100 arm compared to the ipilimumab arm, OS in the ipilimumab arm 
compared to the gp100 arm, best overall response rate (BORR) at Week 24 between each 
of the study arms, and duration of response.  
Of the randomized subjects, 61%, 59%, and 54% in the ipilimumab + gp100, ipilimumab, 
and gp100 arms, respectively, were men. Twenty-nine (29%) percent were  65 years of 
age, the median age was 57 years, 71% had M1c stage, 12% had a history of previously 
treated brain metastasis, 98% had ECOG performance status of 0 and 1, 23% had received 
aldesleukin and 38% had elevated LDH level. Sixty-one (61%) percent of subjects 
randomized to either ipilimumab -containing arm received all 4 planned doses. The median 
duration of follow-up was 8.9 months. 
The OS results are shown in Table 5 and Figure 2. 
Table 5: 
MDX010-20 Overall Survival Results 
 
Ipilimumab 
n = 137 
Ipilimumab + gp100 
n = 403 
gp100 
n = 136 
Hazard Ratio (vs gp100) 
 
(95% CI) 
0.66 
(0.51, 0.87) 
0.68 
(0.55, 0.85) 
 
 
p-value 
p = 0.0026a 
p = 0.0004 
 
Hazard Ratio (vs ipilimumab) 
 
(95% CI) 
 
1.04 
(0.83, 1.30) 
 
Median (months) 
 
(95% CI) 
10 
(8.0, 13.8) 
10 
(8.5, 11.5) 
6 
(5.5, 8.7) 
a Not adjusted for multiple comparisons. 
 

 
 
28 
Figure 2: 
MDX010-20 - Overall Survival by Treatment (ITT Population) 
 
 
The best overall response rate (BORR) as assessed by the investigator was 5.7% (95% CI: 
3.7%, 8.4%) in the ipilimumab + gp100 arm, 10.9% (95% CI: 6.3%, 17.4%) in the 
ipilimumab arm, and 1.5% (95% CI: 0.2%, 5.2%) in the gp100 arm. The median duration 
of response was 11.5 months in the ipilimumab + gp100 arm and has not been reached in 
the ipilimumab or gp100 arm. 
 
1.3.7.c CA184024 (Phase 3, previously untreated melanoma, 10 mg/kg) 
CA184024 evaluated the addition of 10 mg/kg ipilimumab to dacarbazine in patients with 
previously untreated, metastatic melanoma. A total of 502 patients were randomized to 
receive up to 8 cycles of dacarbazine 850 mg/m2 q3w, with either ipilimumab 10 mg/kg or 
placebo cycles 1-4, and as maintenance after completion of chemotherapy.  
The two arms were well balanced regarding most baseline characteristics, as shown in 
Table 6. 

 
 
29 
Table 6: 
CA184024 Baseline Characteristics 
 
Ipilimumab + DTIC 
n = 250 
Placebo + DTIC 
n = 252 
Age (years) 
 
 
 Mean 
57.5 
56.4 
Gender (%) 
 
 
 Male 
60.8 
59.1 
 Female 
39.2 
40.9 
M Stage (%) 
 
 
 M0 
2.4 
3.2 
 M1a 
14.8 
17.1 
 M1b 
25.6 
24.6 
 M1c 
57.2 
55.2 
ECOG PS (%) 
 
 
 0 
70.8 
71.0 
 1 
29.2 
29.0 
LDH (%) 
 
 
  ULN  
62.8 
55.6 
 > ULN  
37.2 
43.7 
  2x ULN 
86.4 
85.3 
 > 2x ULN 
13.6 
13.9 
Prior adjuvant therapy (%) 
26.4 
26.6 
Prior therapy for advanced disease (%) 
0 
0 
 
Patients on the ipilimumab arm received a median of 3 ipilimumab induction doses, versus 
4 placebo induction doses on the placebo arm. A total of 17.4% and 21.1% of patients 
continued to receive maintenance ipilimumab or placebo, for a median of 4 and 2 doses, 
respectively. The number of patients who received all 8 dacarbazine doses was 12.2% in 
the ipilimumab arm, and 21.5% in the placebo arm. 
The study met its primary end-point of prolonging overall survival in patients treated with 
ipilimumab (HR 0.72 (95% CI, 0.59 – 0.87), median OS 11.2 vs 9.1 months, p = 0.0009). 
The OS Kaplan-Meier curve is presented in Figure 3. 

 
 
30 
Figure 3: 
CA184024 Kaplan-Meier Plot of Overall Survival - All 
Randomized Subjects 
 
 
One, two and three year survival rates were 47.3%, 28.5% and 20.8% in the ipilimumab 
arm, and 36.3%, 17.9% and 12.2% in the placebo arm. 
PFS, a secondary end-point, was also prolonged by the addition ipilimumab, HR 0.76 (95% 
CI, 0.63 - 0.93). The median PFS was 2.8 months in the ipilimumab and vs 2.6 months in 
the placebo arm, p = 0.006. 
BORR was increased from 10.3% in the placebo arm to 15.2% in the ipilimumab arm 
(Table 7). More importantly, duration of response was more than twice as long in the 
ipilimumab arm (19.3 months) than in the placebo arm (8.1 months). 
PROPORTION ALIVE
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46
48
Ipilimumab + DTIC 
Placebo + DTIC 
Months 

 
 
31 
Table 7: 
CA184024 Tumor Response 
 
Ipilimumab + DTIC 
n = 250 
Placebo + DTIC 
n = 252 
Disease Control Rate, n (%) 
83 (33.2) 
76 (30.2) 
BORR (CR + PR), n (%) 
38 (15.2) 
26 (10.3) 
 Complete response 
4 (1.6) 
2 (0.8) 
 Partial response 
34 (13.6) 
24 (9.5) 
 Stable disease 
45 (18.0) 
50 (19.8) 
 Progressive disease 
111 (44.4) 
131 (52.0) 
Duration of response, months 
19.3 
8.1 
 
1.3.7. d 10 mg/kg Dosing with Ipilimumab 
In melanoma, Phase 3 studies show improved survival at both 3 mg/kg (study 
MDX010-20) as well as with 10 mg/kg (study CA184024). Several additional conducted 
trials studied the efficacy and safety of 10 mg/kg dosing, and additional information gained 
from these trials is listed below: 
 A dose of 10 mg/kg is necessary to ensure a blockade of the CTLA-4 pathway: in vitro 
a concentration of 20 g/mL of ipilimumab was the minimal concentration able to fully 
abrogate the binding of CTLA-4 to B7.1 and B7.2. With a dose of 3 mg/kg q3w 30% 
achieved a trough concentration of ipilimumab greater than 20 g/mL, compared to 
95% of subjects treated at 10 mg/kg q3w. 
 In addition, in all ipilimumab trials examined to date, mean Absolute Lymphocyte 
Count (ALC) increased after ipilimumab treatment throughout the 12-week induction-
dosing period, in a dose-dependent manner. In an analysis of ipilimumab at 0.3, 3, or 
10 mg/kg in melanoma studies CA184007, CA184008, and CA184022 combined, the 
rate of change in ALC after ipilimumab treatment was significantly associated with 
dose (p = 0.0003), with the largest rate at 10 mg/kg ipilimumab. Moreover, the rate of 
change in ALC over the first half of the induction-dosing period was significantly 
associated with clinical activity in these studies (p = 0.009), where clinical activity was 
defined as CR, PR, or prolonged SD (ie, SD lasting at least 6 months from first dose). 
Although these analyses alone could not determine whether the rate of change in ALC 
was specifically associated with clinical activity in response to ipilimumab treatment, 
as opposed to being generally prognostic, these results do suggest a potential benefit to 
higher rates of ALC increase after ipilimumab treatment. Among the 3 doses evaluated, 
10 mg/kg ipilimumab led to the greatest such rates. 
 In the 3 primary studies conducted in advanced melanoma (CA184007, CA184008, 
and CA184022), subjects treated with 10 mg/kg during the induction period had the 

 
 
32 
highest response, disease control rates, median OS as well as 1-year and 2-year survival 
rates compared to other doses. The CA184022 data are summarized in Table 8. 
 
Table 8: 
Summary of Phase 2 Response Data in Melanoma (CA184022) 
 
10 mg/kg 
(n = 72) 
3 mg/kg 
(n = 72) 
0.3 mg/kg 
(n = 73) 
BORR (mWHO) – % 
(95% CI) 
11.1 
(4.9 - 20.7) 
4.2 
(0.9 - 11.7) 
0 
(0.0 - 4.9) 
DCR (mWHO) – % 
(95% CI) 
29.2 
(19.0 - 41.1) 
26.4 
(16.7 - 38.1) 
13.7 
(6.8 - 23.8) 
Survival rate at 1 year - % 
%, 95% CI 
48.64 
(36.84, 60.36) 
39.32 
(27.97, 50.87) 
39.58 
(28.20, 51.19) 
Survival rate at 2 year - % 
%, 95% CI 
29.81 
(19.13, 41.14) 
24.20 
(14.42, 34.75) 
18.43 
(9.62, 28.22) 
Overall median survival 
95%CI (months) 
11.43 
(6.90, 16.10) 
8.74 
(6.87, 12.12) 
8.57 
(7.69, 12.71) 
Finally, the dose and schedule in study CA184156 is the one that was evaluated in the 
signal finding study CA184041, with an acceptable safety profile and improvement of 
irPFS and OS. 
Treatment with ipilimumab has demonstrated clinically important and durable tumor 
responses in several malignancies including melanoma, prostate cancer, and renal cell 
carcinoma.  
1.3.7.e Advanced Melanoma 
Ipilimumab prolonged survival in subjects with pre-treated advanced melanoma are based 
on results from MDX010-20 (Phase 3) supported by data from Phase 2 studies; the primary 
efficacy and safety studies are summarized in Table 9.16-23 The primary endpoint in 
MDX010-20 was OS, which was also a key secondary endpoint in Phase 2 studies. 
Table 9: 
Studies Supporting the Efficacy and Safety of Ipilimumab in 
Subjects with Advanced Melanoma 
 
 
 
 
# Randomized or Enrolled/Treated 
Study No. 
(Phase) 
Populations 
Primary 
Efficacy 
Endpoint 
Doses Studies 
3 mg/kg 
10 
mg/kg 
Total 

 
 
33 
Table 9: 
Studies Supporting the Efficacy and Safety of Ipilimumab in 
Subjects with Advanced Melanoma 
 
 
 
 
# Randomized or Enrolled/Treated 
MDX010-20 
(Phase 3) 
HLA-
A2*0201-
positive, 
previously 
treated, 
unresectable 
Stage III or 
IV 
melanoma 
OS 
3 mg/kg q3 wk x 
4  gp100 
(induction) 
followed by re-
induction  
540/512 
--/-- 
676/643a 
CA184022 
(Phase 2)  
Previously 
treated, 
unresectable 
Stage III or 
IV 
melanoma  
BORR 
0.3, 3, or 10 
mg/kg q3 wk x 4 
(induction) 
followed by 
maintenance 
dosing q12 wk 
72/71 
72/71 
217/214 
CA184004 
(Phase 2) 
Biomarker 
Study 
Unresectable 
Stage III or 
IV 
melanoma  
BORR 
3 or 10 mg/kg q3 
wk x 4 (induction) 
followed by 
maintenance 
dosing q12 wk 
40/40 
42/42 
82/82 
CA184008 
(Phase 2) 
Previously 
treated 
unresectable 
State III or 
IV 
melanoma 
BORR 
10 mg/kg q3 wk x 
4 (induction) 
followed by 
maintenance 
dosing q12 wk 
--/-- 
155/155 
155/155 
CA184007 
Unresectable 
Stage III or 
IV 
melanoma 
BORR 
10 mg/kg q3 wk x 
4  budesonide 
(induction) 
followed by 
maintenance 
dosing q12 wk 
--/-- 
115/115 
115/115 
Additional Studies  
MDX010-
08(Phase 2) 
Chemothera
py-naive 
advanced 
melanoma 
ORR 
3 mg/kg q4 
wk x 4  
DTIC 
(induction) 
78/74 
--/-- 
78/74 
CA184042 
(Phase 2) 
Stage IV 
melanoma 
with brain 
metastases 
DCR 
10 mg/kg q3 
wk x 4 
(induction) 
followed by 
maintenance 
dosing q12 
wk 
--/-- 
28/28b 
28/28b 

 
 
34 
Table 9: 
Studies Supporting the Efficacy and Safety of Ipilimumab in 
Subjects with Advanced Melanoma 
 
 
 
 
# Randomized or Enrolled/Treated 
MDX010-28 
(Phase 2) 
Survival 
Follow-up 
Study 
Subjects 
enrolled in 
earlier 
Medarex 
studies, 
including 
MDX010-08 
and 
MDX010-
15c 
OS 
N/A 
--/N/A 
--/NA 
--/N/A 
BORR = best overall response rate; DCR = disease control rate; DTIC = dacarbazine; N/A = not applicable; 
ORR = overall response rate; OS = overall survival; PK = pharmacokinetics. 
a Total includes 136 randomized/131 treated subjects in the gp100 treatment group. 
b Information is presented only for subjects enrolled in MDX010-20, Arm A. 
c MDX010-15 was primarily a PK study that evaluated ipilimumab at single and multiple doses.  
Source:  Reference 16-23 
 
 
1.3.7.f Rationale for combining Nivolumab with ipilimumab 
The combination of nivolumab and ipilimumab was chosen as an experimental arm 
because of preclinical and preliminary clinical evidence suggesting synergy between 
nivolumab and ipilimumab. While PD-1 and CTLA-4 are both co-inhibitory molecules, 
evidence suggests that they use distinct mechanisms to limit T cell activation. Preliminary 
indirect data from peripheral T cell assessments suggest that a given T-cell checkpoint 
inhibitor may modulate host immune cell phenotype rendering them more susceptible to 
alternate checkpoint inhibitors and thereby enhancing anti-tumor activity. Specifically, 
nivolumab increased peripheral CTLA-4+ and regulatory T cells in subjects without 
clinical response in CA209006.48 In a preclinical melanoma model, anti-CTLA-4 therapy 
increased PD-1+, PD-L1+ and CTLA-4+ tumor infiltrating T cells.49 In addition, in the 
Phase 2 ipilimumab monotherapy study CA184004, increases in tumor infiltrating 
lymphocytes (TILs) and interferon-α-inducible genes were observed following treatment 
with ipilimumab, and PD-L1 positive tumor cells co-localize with both TILs and IFN-α 
expression in metastatic melanoma.50, 51,52 
The preliminary clinical evidence has demonstrated a higher frequency of patients with 
substantial tumor burden reduction for the combination of nivolumab and ipilimumab. 

 
 
35 
Improved overall survival associated with substantial tumor burden reduction has been 
noted with immunotherapies. For instance, improved overall survival has been noted in 
metastatic melanoma subjects obtaining a complete response to IL-2.53 If this observation 
is also applicable to treatment with nivolumab combined with ipilimumab then there could 
also be the potential for large improvements in overall survival compared to ipilimumab. 
Dose and Schedule Rationale 
In CA209004, the 3 mg/kg nivolumab and 3 mg/kg ipilimumab cohort exceeded the 
maximum tolerated dose per protocol. In CA209004, while both Cohort 2 (1 mg/kg 
nivolumab + 3 mg/kg ipilimumab) and Cohort 2a (3 mg/kg nivolumab + 1 mg/kg 
ipilimumab) had similar clinical activity, 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 3mg/kg every 2 weeks until progression was chosen. Exposure-response 
analysis of nivolumab monotherapy across dose ranges of 1 mg/kg to 10 mg/kg reveals 
similar clinical activity while exposure-response analysis of 0.3 mg/kg, 3 mg/kg, and 10 
mg/kg of ipilimumab monotherapy have demonstrated increasing activity with increase in 
dose in the phase 2 study CA184022.54 Therefore, theoretically 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 has a similar dose and schedule as that in CA209004 for the first 12 
weeks, increasing the likelihood of replicating the clinical activity seen in the CA209004 
study. Based on the clinical activity in CA209004, the majority of responses to the 
combination of nivolumab and ipilimumab occur in the first 12 weeks. Given the 
uncertainty of whether the ipilimumab administered past week 12 contributes to the clinical 
benefit and the fact that the approved schedule for ipilimumab is every 3 weeks for a total 
of four doses in the FDA and EMA approved label dosing section, ipilimumab will only 
be administered every 3 weeks for a total of 4 doses. Nivolumab monotherapy treatment 
every two weeks until progression was studied in CA209003 and is implemented program-
wide across the nivolumab monotherapy Phase 3 registrational trials.  
 
Nivolumab monotherapy has been extensively studied in a number of tumor types 
including non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), 
and colorectal cancer (CRC) with body weight normalized dosing (mg/kg). Nivolumab 
pharmacokinetics (PK) and exposures of subjects in these studies have been characterized 
by populationpharmacokinetic (PPK) analysis of data collected in these studies, together 

 
 
36 
with PK data from several Phase 1, 2, and 3 clinical studies of nivolumab monotherapy in 
solid tumors. PPK analyses have shown that the PK of nivolumab are linear, with dose 
proportional exposures over a dose range of 0.1 mg/kg to 10 mg/kg, and are similar across 
tumor types. Nivolumab clearance and volume of distribution were found to increase with 
increasing body weight, but the increase was less than proportional, indicating that a mg/kg 
dose represents an over-adjustment for the effect of body weight on nivolumab PK. Given 
the relationship between nivolumab PK and body weight, a flat dose is expected to lead to 
lower exposures in heavier patients, relative to the exposures in lighter patients. 
Using the PPK model, nivolumab steady-state trough, peak and time-averaged 
concentration (Cminss, Cmaxss, and Cavgss, respectively) were predicted for a flat 
nivolumab dose of 240 mg Q2W and compared to those following administration of 3 
mg/kg Q2W in NSCLC, melanoma, and RCC subjects. A dose of 240 mg nivolumab is 
identical to a dose of 3 mg/kg for subjects weighing ~ 80 kg, which is the approximate 
median body weight of subjects in the Phase 2 and 3 BMS clinical studies of nivolumab 
monotherapy. From the simulations, the geometric mean values of Cminss, Cmaxss, and 
Cavgss with flat dosing are slightly (< 15%) higher than that produced by a 3 mg/kg dose, 
and the coefficient of variation (cv%) in these measures of exposure are only slightly (< 
10%) greater than that of 3 mg/kg dosing. Given the similarity of nivolumab PK across 
tumor types and the similar exposures predicted following administration of a 240 mg flat 
dose compared to 3 mg/kg, it is expected that the safety and efficacy profile of nivolumab 
following a flat dose will be similar to that of 3 mg/kg nivolumab dose. 
Across the various tumor types in the BMS clinical program, nivolumab has been shown 
to be safe and well tolerated up to a dose level of 10 mg/kg, and the relationship between 
nivolumab exposure produced by 3 mg/kg and efficacy has been found to be relatively flat. 
Taken together, the PK, safety, and efficacy data indicate that the safety and efficacy profile 
of flat nivolumab dose every 2 weeks will be similar to that of a 3 mg/kg nivolumab every 
2 weeks. In this study after completion of the combination portion of the study, all subjects 
will receive flat dose 480 mg nivolumab every 4 weeks (Q4W), which provides a more 
convenient dosing regimen for subjects. Based on PK modeling and simulations, 
administration of nivolumab 480 mg Q4W will be started after steady state is achieved 
with the combination regimen. While 480 mg Q4W is predicted to provide greater 
(approximately 20%) maximum steady state concentrations and lower (approximately 
10%) steady state trough concentrations, these exposures are predicted to be within the 
exposure ranges observed at doses up to 10 mg/kg Q2W used in the Phase 1 nivolumab 
clinical program, and are not considered to put subjects at increased risk. Similar to 

 
 
37 
the nivolumab Q2W dosing monotherapy regimen, the exposures predicted following 
administration of nivolumab 480 mg Q4W, are on the flat part of the exposure-response 
curves for previously investigated tumors, melanoma and NSCLC, and are not predicted 
to affect efficacy. Based on these data, nivolumab 480 mg Q4W is expected to have similar 
efficacy and safety profiles to nivolumab 3 mg/kg Q2W. 
Hence, doubling the dose of nivolumab from 240 mg to 480 mg would extend the dosing 
interval from 2 weeks to 4 weeks. Thus a flat dose of 480 mg every 4 weeks is 
recommended for investigation in the maintenance phase of this study.  
1.3.7. g 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 also 
with ipilimumab monotherapy. 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.  
  
1.4 Overall Risk/Benefit Assessment 
There continues to be a significant unmet need for patients with previously untreated, 
unresectable or metastatic uveal melanoma. 
Nivolumab monotherapy has demonstrated clinical activity across several tumor types, 
including advanced prior treated melanoma, with objective response rates of 20 - 41% in 
106 melanoma subjects treated at various dose levels in CA209003. Nivolumab has also 
demonstrated a manageable safety profile. The most common AEs included fatigue, rash, 
pruritis, diarrhea, and nausea. 

 
 
38 
The combination of nivolumab and ipilimumab has the potential for increased benefit 
compared to both ipilimumab monotherapy and nivolumab monotherapy. Preliminary 
analysis of the evaluable CA209004 subjects revealed that approximately 33% of the 
subjects had >80% tumor reductions in target lesions by week 12. This compares favorably 
to < 2% for 3 mg/kg ipilimumab monotherapy based on the CA184020 (N=540) and <3% 
for nivolumab monotherapy based on the CA209003. However, the combination of 
nivolumab and ipilimumab also has the potential for increased frequencies of adverse 
events. 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. Although the preliminary data suggests an increase in adverse event 
frequency of nivolumab combined with ipilimumab compared to ipilimumab monotherapy 
or nivolumab monotherapy, there were no unexpected adverse events noted in the 
combination of nivolumab and ipilimumab. In addition, many of the Grade 3-4 adverse 
events associated with the nivolumab combined with ipilimumab were laboratory in nature, 
without clinical sequalae and adverse events have been manageable and reversible 
following intervention dose delays or with systemic steroid treatment. 
Evaluating the combination of nivolumab and ipilimumab will provide clinical data 
allowing clinicians to select the appropriate treatment for each patient based on the 
individual risk-benefit ratio. The robust clinical activity demonstrated by nivolumab 
monotherapy and the promising clinical activity of nivolumab combined with ipilimumab 
in subjects with advanced melanoma in combination with the manageable safety profile 
and the lack of approved survival-prolonging agents for a large segment of the previously 
untreated population supports the further development of nivolumab and nivolumab 
combined with ipilimumab in subjects with previously untreated, unresectable or 
metastatic melanoma. 
1.5 Uveal Melanoma 
Uveal melanoma is the most common primary intraocular malignant tumor in adults and 
the second most common type of primary malignant melanoma in the body.  It represents 
five to six percent of all melanoma diagnoses.  The incidence of uveal melanoma in the 
world is approximately 4,800 persons per year with nearly 2,000 cases diagnosed in North 
America annually.  Metastasis is via vascular spread, and approximately 40-50% of 
patients with uveal melanoma will ultimately develop distant disease.  The liver is involved 
in up to 95% of individuals who develop metastatic disease.  The clinical course of patients 
with uveal melanoma is determined by progression of the disease in the liver.  Once 
metastatic disease is identified, the median survival of patients with liver metastases is six 

 
 
39 
to seven months, despite therapy, with a dismal one-year survival of approximately 10-
15%.25, 26, 33 
Immunotherapy using checkpoint blockade inhibitors have made significant headway in 
cutaneous melanoma but their relevance in melanomas of rare subtypes, including uveal 
melanoma, remains unstudied in a prospective fashion.  Anecdotal reports from expanded 
access programs and case reports of uveal melanoma patients treated with ipilimumab at 
both 3 mg/kg and 10 mg/kg demonstrate modest clinical activity at best with responses no 
more than 6%, CA184-187 was the first prospective ipilimumab trial in the world dedicated 
solely to uveal melanoma patients.  After enrollment of 20 patients however, no 
documented responses were noted at both 3 mg/kg and 10 mg/kg.   
 
Because of rationale behind combination checkpoint blockade inhibition and the notable 
clinical activity in cutaneous melanoma with a 1-year overall survival approaching that of 
targeted therapies (69% 1-year OS presented by Sznol et al. ASCO 2014), it is possible 
that monotherapy checkpoint blockade may not be enough to overcome tumor progression 
in uveal melanoma and that combination immunotherapy is in fact the necessary approach.  
Indeed, reports of small series of uveal melanoma patients on monotherapy anti-PD-1 
clinical trials to date have failed to demonstrate any responses (nivolumab, MK-3475).   
Combination checkpoint blockade with nivolumab and ipilimumab at doses established in 
cutaneous melanoma warrant investigation in a prospective fashion for metsatatic uveal 
melanoma patients.   
The overall risk-benefit ratio for patients entering this protocol is therefore at least 
comparable to and possibly better than alternative options, specifically for uveal 
melanoma, where no standard therapies exist.  Therefore, this protocol is at least 
comparable to the consensus recommendations for this population to enroll on some form 
of a clinical trial. 
1.6 Study Rationale 
Metastatic uveal melanoma is uniformly fatal and median overall survival with current 
therapies remains poor (6 months) with 10-15% of patients surviving at one year.  
Ipilimumab has been safely used in uveal melanoma patients in the expanded access 
program both in the United States and in Europe. Anti PD-1 early clinical trials have 
enrolled few uveal melanoma patients with no notable responses, although administration 
was safe and tolerable. Combination nivolumab plus ipilimumab in cutaneous melanoma 
is marked by early tumor responses with significant regression in tumor burden.  However, 

 
 
40 
uveal melanoma patients were not enrolled on this combination study.  As noted in 
cutaneous melanoma, the combination of two checkpoint inhibitors may result in early and 
deep tumor responses for the population of patients with advanced uveal melanoma.   
Metastatic uveal melanoma patients with at least one  measureable lesion will be treated 
with nivolumab plus ipilimumab until disease progression or until unmanageable toxicity 
occurs. 
 
2 STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective of this study is overall response rate  
 
2.2 Secondary Objectives 
Secondary objectives include Safety and tolerability of combination, progression-free 
survival, median overall survival, and one-year overall survival. 
 
2.3 Exploratory Objectives 
Exploratory Objectives include tissue and blood correlates to define immune infiltration 
and signatures as a result of treatment with nivolumab plus ipilimumab. 
3. STUDY DESIGN 
3.1 Screening and registration 
Interested patients with uveal melanoma will be screened for eligibility as defined in 
Section 4.  If all criteria are met, the patient will sign consent and be registered into the 
central database, Clinical Oncology Research System (CORe).   
3.2 
Study Schema 
This is a Phase II study of nivolumab combined with ipilimumab for metastatic uveal 
melanoma.  
See illustrated schema on the following page. 

 
 
41 
 
STUDY SCHEMA: 
 
Eligible metastatic uveal melanoma 
patients
Induction: 
Nivolumab 1 mg/kg + Ipilimumab 3 
mg/kg Q3W x 4 doses 
Maintenance: 
Nivolumab 480mg/Q4W

 
 
42 
3.3 Treatment 
Nivolumab is to be administered as a 60-minute IV infusion, using a volumetric pump 
with a 0.2/0.22 micron in-line filter at the protocol-specified dose. The drug can be 
diluted with 0.9% normal saline for delivery but the total drug concentration of the 
solution cannot be below 0.35 mg/ml. It is not to be administered as an IV push or bolus 
injection. At the end of the infusion, flush the line with a sufficient quantity of normal 
saline. 
 
Ipilimumab is to be administered as a 90-minute IV infusion, using a volumetric pump with 
a 0.2 to 1.2 micron in-line filter at the protocol-specified dose. The drug can be diluted with 
0.9% normal saline or 5% Dextrose Injection to concentrations between 1 mg/mL and 4 
mg/mL. It is not to be administered as an IV push or bolus injection. Care must be taken to 
assure sterility of the prepared solutions, since the drug product does not contain any 
antimicrobial preservatives or bacteriostatic agents. At the end of the infusion, flush the 
line with a sufficient quantity of normal saline or 5% dextrose solution. 
 
When both study drugs are to be administered on the same day, separate infusion bags and 
filters must be used for each infusion. Nivolumab is to be administered first. The nivolumab 
infusion must be promptly followed by a saline flush to clear the line of nivolumab before 
starting the ipilimumab infusion. 
 
Baseline weight will be used to calculate all induction doses unless weight varies by +/- 
10% from baseline.  In that case, actual weight will be used. 
 
 
3.2.1.a Induction Phase 
During the induction phase, patients will be treated with nivolumab 1 mg/kg plus 
ipilimumab 3 mg/kg (+/- 7 days) for a total of four doses (week 1, 4, 7, 10).  The induction 
phase continues through week 12.  
During the induction phase, patients will also have a mandatory biopsy of tumor tissue for 
exploratory immune biomarker studies. This biopsy can occur any time after cycle 1 until 
the end of cycle 4 (weeks 4-12). 
3.2.1.b Maintenance Phase 
For patients who have not experienced disease progression, or unmanageable toxicity by 
week 12, a maintenance phase will begin.  Maintenance treatment consists of nivolumab 

 
 
43 
monotherapy 480 mg/ every 4 weeks for up to 104 weeks or until disease progression or 
unmanageable toxicity as deemed by the clinical investigator.  
During the maintenance phase and at the end of the study, patients have the option to 
undergo an additional biopsy of tumor tissue for exploratory biomarker studies. 
 
3.2.1.c General Treatment Instructions 
 As durable disease stabilization and/or objective tumor response can be seen after 
early progression before week 12, it is recommended that, in the absence of 
dose-limiting toxicities (eg, serious immune-mediated adverse reactions), all four 
doses of nivolumab plus ipilimumab be administered over the initial 12 weeks even 
in the setting of apparent clinical progression, providing the subject’s performance 
status remains stable. 
 All metastatic subjects who enter the induction period, including those who may 
have discontinued treatment for drug-related AEs and/or who have evidence of 
clinical progression during the induction period, should obtain a 12-week tumor 
assessment. 
 Based on clinical experience in the ongoing and completed melanoma studies, the 
following recommendations apply for subject management in light of the week 12 
or later tumor assessments: 
 The appearance of new lesions in subjects with other stable or shrinking 
baseline tumor burden may be experiencing clinical benefit and should continue 
in follow-up and/or maintenance therapy before alternative anti-cancer agents 
are considered. These subjects can be seen to have continued tumor shrinkage 
in follow-up scans. 
 As long as overall tumor burden is stable or decreasing, subjects should remain 
in follow-up and/or maintenance (see below), even in the presence of new 
lesions. 
 Clinical progression warranting alternative anti-cancer treatment should be 
considered only in subjects whose overall tumor burden appears to be 
substantially increased and/or in subjects whose performance status is 
decreased. 
 
3.4 Follow-up (duration of study) 
 Subjects who are no longer receiving treatment and are removed from the study 
because of unacceptable toxicity (refractory Grade > 3 immune-mediated adverse 
reactions) or due to investigator or his designee judgment are managed in 
follow-up. Efficacy assessments for these subjects during follow-up are as per the 
standard of care. Date of death is recorded. 
 Subjects who discontinue treatments should be followed until death or the closure 
of the study (whichever is first). 

 
 
44 
 Subjects who are no longer receiving treatment because of clinical progression or 
who have switched to alternative treatment are not followed formally except to 
record the date of death. 
 All subjects who come off study for any reason will be followed for at least 60 days, 
which is equal to 4 half –lives of the longest drug. 
4 SUBJECT SELECTION CRITERIA 
For entry into the study, the following criteria MUST be met. Any exceptions from the 
protocol-specific selection criteria must be approved by the Principal Investigator, the IND 
office medical monitor and/or the Institutional Review Board (IRB) before enrollment. 
4.1 Inclusion Criteria 
1. Willing and able to give written informed consent. 
2. History of uveal melanoma and documented metastatic disease with at least one 
measurable lesion is required defined as ≥ 1 cm x 1 cm (on spiral CT or equivalent). 
3. Any number of prior therapies is allowed. 
4. Required values for initial laboratory tests:  
 WBC 
 2000/uL 
 ANC 
 1500/uL 
 Platelets 
 100 x 103/uL 
 Hemoglobin 
 9 g/dL  
 Creatinine 
 1.5 x ULN or creatinine clearance (CrCl) > 40 mL/min 
(using the Cockcroft-Gault formula): 
 Female CrCl = (140 - age in years) x weight in kg x 0.85 
72 x serum creatinine in mg/dL 
 Male CrCl = (140 - age in years) x weight in kg x 1.00 
 72 x serum creatinine in mg/dL AST/ALT 
 3 x ULN for patients 
without 
liver 
metastasis, 
                              5 x ULN for liver metastases 
 Bilirubin 
 1.5 x ULN, (except patients with Gilbert’s Syndrome, who 
 
must have a total bilirubin less than 3.0 mg/dL) 
 
5. In suspected patients, no active or chronic infection with HIV, Hepatitis B, or Hepatitis 
C. 
6. Performance status ECOG 0-1.  

 
 
45 
7. Men and women,  18 years of age.  Because no dosing or adverse event data are 
currently available on the use of ipilimumab in patients <18 years of age, minors are 
excluded from this study.  
8. Baseline imaging in the form of CT chest, abdomen, pelvis with oral and intravenous 
contrast within 28 days of study entry.  For patients with a contrast allergy, choice of 
alternative body imaging will be at the discretion of the investigator or his designee.  
MRI of the brain is only needed if clinically indicated. 
9. Prior to start of treatment must be more than 21 days elapsed from surgery, radiation 
therapy, or prior chemotherapy.  More than 42 days elapsed from prior immune therapy 
including vaccines.   
10. Women of childbearing potential (WOCBP) and fertile men with partners of 
childbearing potential must be using an adequate method of contraception to avoid 
pregnancy throughout the study and for up to 26 weeks after the last dose of 
investigational product, in such a manner that the risk of pregnancy is minimized.  
WOCBP include any female who has experienced menarche and who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, 
or bilateral oophorectomy) or is not post-menopausal. Post-menopause is defined 
as: 
 Amenorrhea  12 consecutive months without another cause, or 
 For women with irregular menstrual periods and taking hormone replacement 
therapy (HRT), a documented serum follicle stimulating hormone (FSH) level 
 35 mIU/mL. 
Women who are using oral contraceptives, other hormonal contraceptives (vaginal 
products, skin patches, or implanted or injectable products), or mechanical products 
such as an intrauterine device or barrier methods (diaphragm, condoms, 
spermicides) to prevent pregnancy, or are practicing abstinence or where their 
partner is sterile (e.g., vasectomy) should be considered to be of childbearing 
potential. 
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of βHCG) within 72 hours before the start of 
ipilimumab. 
Men of fathering potential must be using an adequate method of contraception to 
avoid conception throughout the study (and for up to 26 weeks after the last dose 

 
 
46 
of investigational product) in such a manner that the risk of pregnancy is 
minimized. 
Sexually active WOCBP must use an effective method of birth control during the 
course of the study, in a manner such that the risk of failure is minimized.  Before 
enrolling women of childbearing potential in this clinical trial, investigators must 
review the guideline about study participation for WOCBP, which can be found in 
the Good Clinical Practice (GCP) Manual for investigators. The topics include the 
following: 
 
 general information 
 informed consent form 
 pregnancy prevention information sheet 
 drug interactions with hormonal contraceptives 
 contraceptives in current use 
 guidelines for the follow-up of a reported pregnancy 
Prior to study enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an 
unintentional pregnancy.  This discussion will be documented on the informed 
consent form required for study participation.   
In addition, all WOCBP or fertile men with partners of childbearing potential 
should be instructed to contact the investigator immediately if they suspect they or 
their partner might be pregnant (e.g., missed or late menstrual period) at any time 
during study participation. If following initiation of study treatment, it is 
subsequently discovered that a trial patient is pregnant or may have been pregnant 
at the time of exposure to ipilimumab, including during at least 6 half-lives after 
product administration, ipilimumab will be permanently discontinued in an 
appropriate manner. Exceptions to ipilimumab discontinuation may be considered 
for life-threatening conditions only after consultation with the Medical Monitor or 
as otherwise specified in this protocol.    
Protocol-required procedures for study discontinuation and follow-up must be 
performed on the patient unless contraindicated by pregnancy (e.g., x-ray studies). 
Other appropriate pregnancy follow-up procedures should be considered if 
indicated. In addition, the investigator must report to Bristol-Myers Squibb 
follow-up information regarding the course of the pregnancy, including perinatal 
and neonatal outcome. Infants should be followed for a minimum of 8 weeks. 

 
 
47 
4.2 
Exclusion Criteria 
1. Melanomas other than uveal melanoma (i.e. cutaneous, acral lentiginous, mucosal).   
2. Metastatic uveal melanoma patients with bone-only disease.  
3. Any other malignancy from which the patient has been disease-free for less than 
2 years, with the exception of adequately treated and cured basal or squamous cell 
skin cancer, superficial bladder cancer or carcinoma in situ of the cervix, breast, or 
prostate.  
4. Autoimmune disease: Patients with a history of inflammatory bowel disease, 
including ulcerative colitis and Crohn’s Disease, are excluded from this study, as 
are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, 
systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, 
autoimmune vasculitis [e.g., Wegener’s Granulomatosis]; motor neuropathy 
considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia 
Gravis). 
5. Any underlying medical or psychiatric condition, which in the opinion of the 
investigator will make the administration of ipilimumab hazardous or obscure the 
interpretation of AEs, such as a condition associated with frequent diarrhea. 
6. Any non-oncology vaccine therapy used for prevention of infectious diseases (for 
up to 1 month before or after any dose of ipilimumab). 
7. Concomitant therapy with any of the following: tamoxifen, toremifene, IL-2, 
interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; 
immunosuppressive agents; other investigation therapies; or chronic use of 
systemic corticosteroids greater than physiologic replacement doses. Ocular steroid 
use is acceptable. 
a. Concomitant palliative radiation for the purposes of symptom management is 
allowed.  
 
8. Women of childbearing potential (WOCBP), defined above in Section 4.1, who: 
d. are unwilling or unable to use an acceptable method of contraception to avoid 
pregnancy for their entire study period and for up to 26 weeks after cessation of 
study drug, or 
e. have a positive pregnancy test at baseline, or 
f. are pregnant or breastfeeding. 

 
 
48 
9. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) 
for treatment of either a psychiatric or physical (e.g., infectious) illness. 
4.3 Data Safety Monitoring Plan 
MD Anderson Cancer Center (MDACC) will monitor the progress of all clinical 
investigations being conducted under its IND and remain compliant under 
21CFR312.56(b).  The clinical research monitor, who has not had a prior role in the conduct 
of the study, will be assigned to monitor the study and will discuss the frequency of the 
chart review with the PI and the study manager.  For all studies, eligibility and informed 
consent documentation will be reviewed following enrollment of selected subjects.  With 
the exception of eligibility and informed consent review, the PI and the study manager will 
receive notification from the clinical research monitor approximately 2 weeks prior to each 
monitoring visit.  The study coordinator or research nurse will be responsible for providing 
the monitor with any additional supporting documents and regulatory binders.   
The frequency of the monitoring visits will occur every 8-12 weeks or more or less 
frequently as determined by the activity of the clinical trial.  
Source documentation will be reviewed and used to independently verify study data.  Data 
quality will be assessed by measuring it against the standards for optimal data as delineated 
in the research protocol.  Investigator compliance with regulatory requirements and 
guidelines for Good Clinical Practice (GCP) will be assessed. 
The clinical research monitor will complete a written monitoring report following each 
monitoring visit.  The report will include a summary of what the monitor reviewed, any 
significant findings, identified actions taken or to be taken by the research team, and/or 
actions recommended securing compliance.  Emphasis will be placed on clear and 
complete reporting of the findings.  Comments will be made regarding problems or 
concerns affecting the validity or accuracy of the data.   
The final report will be submitted to the MDACC IND Medical Monitor for review.  The 
original signed report will be kept in the IND folder within the IND Office.  A follow-up 
letter identifying unresolved issues will be sent to the PI to be kept in the regulatory binder.  
In order to remain compliant with 21CFR312.56(b) any trial that is being conducted under 
an MDACC-sponsored IND and is discontinued due to investigator noncompliance will 
have official notification set to the FDA.   

 
 
49 
5 STUDY THERAPY 
5.1 
Nivolumab (BMS 936558) 
Nivolumab (BMS-936558) vials must be stored at a temperature of 2or for review.  The 
ori protected from light and freezing. If stored in a glass front refrigerator, vials should be 
stored in the carton. Recommended safety measures for preparation and handling of 
nivolumab include laboratory coats and gloves. 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) and 40 mg/4 mL (10 mg/mL) 
Vials of nivolumab injection must be stored at 2°-8°C (36°-46°F) and protected from 
light, freezing, and shaking.  
 
Undiluted Nivolumab Injection and Diluted Nivolumab Injection in the IV Bag 
The administration of nivolumab infusion must be completed within 24 hours of 
preparation. If not used immediately, the infusion solution may be stored under 
refrigeration conditions (2°-8°C, 36°-46°F) for up to 24 hours, and a maximum of 4 hours 
of the total 24 hours can be at room temperature (20°-25°C, 68°-77°F) and room light. 
The maximum 4-hour period under room temperature and room light conditions includes 
the product administration period.  
Care must be taken to assure sterility of the prepared solution as the product does not 
contain any anti-microbial preservative or bacteriostatic agent. No incompatibilities 
between nivolumab and polyolefin bags have been observed.Nivolumab is to be 
administered before ipilimumab as a 60-minute IV infusion, using a volumetric pump with 
a 0.2/0.22 micron in-line filter at the protocol-specified dose. The drug can be diluted with 
0.9% normal saline for delivery but the total drug concentration of the solution cannot be 
below 0.35 mg/ml. It is not to be administered as an IV push or bolus. 
When the combination of 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 second infusion will always be ipilimumab and will start no 
sooner than 30 minutes after completion of the nivolumab infusion. Ipilimumab may be 
diluted in 0.9% Sodium Chloride Solution or 5% Dextrose solution. Nivolumab may be 
diluted in 0.9% Sodium Chloride Solution.  
The dosing calculations should be based on 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 up to the nearest milligram per institutional 
standard. There will be no dose modifications allowed. 
5.2 
Ipilimumab  
Ipilimumab injection can be used for IV administration without dilution after transferring 

 
 
50 
to a PVC (polyvinyl chloride), non-PVC/non-DEHP (di-(2-ethylhexyl)phthalate) or glass 
containers and is stable for 24 hours at 2-8containersrsistration without dilution after 
transferring storage instructions, refer to 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, using a volumetric pump with 
a 0.2 to 1.2 micron in-line filter at the protocol-specified dose. The drug can be diluted with 
0.9% normal saline or 5% Dextrose Injection to concentrations between 1 mg/mL and 4 
mg/mL. It is not to be administered as an IV push or bolus injection. Care must be taken to 
assure sterility of the prepared solutions, since the drug product does not contain any 
antimicrobial preservatives or bacteriostatic agents. At the end of the infusion, flush the 
line with a sufficient quantity of normal saline or 5% dextrose solution. 
When both study drugs are to be administered on the same day, separate infusion bags and 
filters must be used for each infusion. Nivolumab is to be administered first. The nivolumab 
infusion must be promptly followed by a saline flush to clear the line of nivolumab before 
starting the ipilimumab infusion. 
Ipilimumab infusion will start no sooner than 30 minutes after completion of the nivolumab 
infusion. During the induction phase, subjects may be dosed no less than 19 days between 
doses. 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. 
During the maintenance phase, subjects may be dosed no less than 24 days between doses. 
Subjects may be dosed up to 3 days after the scheduled date if necessary. Subsequent 
dosing should be based on the actual date of administration of the previous dose of drug. 
Ipilimumab may be diluted in 0.9% Sodium Chloride Solution or 5% Dextrose solution. 
Nivolumab may be diluted in 0.9% Sodium Chloride Solution. 
5.2.1 Dose Calculations 
Premedications should not be routinely administered prior to dosing of study drugs. See 
Section 4.5.6 for subsequent premedication recommendations following a nivolumab or 
ipilimumab-related infusion reaction.   
The dosing calculations should be based on 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 

 
 
51 
recalculated. All doses should be rounded up to the nearest milligram per institutional 
standard. There will be no dose modifications allowed. 
5.2.2 Dose Delay Criteria 
Dose reductions or dose escalations are not permitted.   
Dose delay criteria apply for all drug-related adverse events (regardless of whether or not 
the event is attributed to nivolumab, ipilimumab, or both). All study drugs must be 
delayed until treatment can resume (see Section 4.3.4.) 
Nivolumab and ipilimumab administration should be delayed for the following: 
During Induction, subjects may be dosed no less than 19 days between doses. 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. 
During Maintenance, subjects may be dosed no less than 24 days between doses.  
Subjects may be dosed up to 3 days after the scheduled date if necessary. Subsequent 
dosing should be based on the actual date of administration of the previous dose of drug. 
 
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 who have not experienced a Grade 3 drug-related skin AE may 
resume treatment in the presence of Grade 2 skin toxicity 
 Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose 
delays for reasons other than a 2-grade shift in AST/ALT or total bilirubin may 
resume treatment in the presence of Grade 2 AST/ALT OR total bilirubin 
 Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 4.3.5)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 may resume treatment 

 
 
52 
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 next 
scheduled timepoint per protocol, the next scheduled timepoint will be delayed until 
dosing resumes.  If treatment is delayed > 6 weeks, the subject must be permanently 
discontinued from study therapy, except as specified in Section 5.2.3. 
5.2.3 Discontinuation of Study Therapy 
Subjects MUST be discontinued from study therapy AND withdrawn from the study for 
the following reasons: 
 Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment 
 Any Grade 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 
 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 of pancreatitis. It is recommended to consult with the BMS 
Medical Monitor for Grade 4 amylase or lipase abnormalities. 

 
 
53 
 Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset 
 Any 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 PI will discuss feasibility with the sponsor.. 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 intercurrent illness which, in the judgment 
of the Investigator, presents a substantial clinical risk to the subject with continued 
nivolumab or ipilimumab dosing. 
 Withdrawal of informed consent (subject’s decision to withdraw for any reason). 
 Any clinical adverse event, laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued treatment with study therapy is not 
in the best interest of the subject. 
 Pregnancy 
 All WOCBP should be instructed to contact the investigator immediately if they 
suspect they might be pregnant (e.g., missed or late menstrual period) at any time 
during study participation. Institutional policy and local regulations should 
determine the frequency of on study pregnancy tests for WOCBP enrolled in the 
study. 
 The investigator must immediately notify BMS in the event of a confirmed 
pregnancy in a patient participating in the study. 
 Termination of the study by Bristol-Myers Squibb (BMS). 
 Imprisonment or the compulsory detention for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness. 
 
5.2.4 Permanent Discontinuation of Ipilimumab 
5.2.4.a Permanent Discontinuation for Related Adverse Events  

 
 
54 
Refer to Appendix B for algorithms recommended for utilization in CA184-187.  
Permanently discontinue treatment for any of the following: 
 Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 
mg prednisone or equivalent per day. 
 Severe or life-threatening adverse reactions, including any of the following: 
 Radiographic or histologic diagnosis of colitis with abdominal pain, fever, ileus, or 
peritoneal signs; increase in stool frequency (7 or more over baseline) or 
incontinence unable to be mitigated with corticosteroids, gastrointestinal 
hemorrhage, or gastrointestinal perforation 
 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times the 
upper limit of normal or total bilirubin >3 times the upper limit of normal 
 Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full 
thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations 
 Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia 
gravis 
 Severe immune-mediated reactions involving any organ system (eg, nephritis, 
pneumonitis, pancreatitis, non-infectious myocarditis) 
 Immune-mediated 
ocular 
disease 
that 
is 
unresponsive 
to 
topical 
immunosuppressive therapy (eg, ocular steroids) 
 Any adverse event, laboratory abnormality or intercurrent illness which, in the 
judgment of the investigator, presents a substantial clinical risk to the patient with 
continued dosing.  
 The development of progression (irPD) in the global tumor burden confirmed by 
serial imaging 4-6 weeks later and/or clinical deterioration of subject’s condition 
such that further benefit from ipilimumab dosing is unlikely or requires a change 
of therapy. 
Please refer to section 5.1.7 and the IB for specific AE management algorithms. 
The following neurological adverse event requires permanent discontinuation of 
ipilimumab and defines unacceptable neurotoxicity: 
 Any motor neurologic toxicity >/= Grade 3 regardless of causality 
 Any >/= Grade 3 treatment related sensory neurologic toxicity 
 
Please refer to section 5.1.7 and the IB for specific AE management algorithms. 
 
5.2.4.b Exceptions to Permanent Discontinuation 
 
 Potentially reversible inflammation (< Grade 4), attributable to a local anti-tumor 
reaction and a potential therapeutic response. This includes inflammatory reactions at 

 
 
55 
sites of tumor resections or in draining lymph nodes, or at sites suspicious for, but not 
diagnostic of metastasis. 
 Hospitalization for ≤ Grade 2 adverse events where the primary reason for 
hospitalization is to expedite the clinical work-up. 
 Patients with the following conditions where in the investigator’s opinion continuing 
study drug administration is justified: 
 Ocular toxicity that has responded to topical therapy (eg, ocular steroids). 
 Endocrinopathies where clinical symptoms are controlled with appropriate 
hormone replacement therapy. Note: Ipilimumab may not be restarted while the 
patient is being treated with systemic corticosteroids except for patients on stable 
doses of hormone replacement therapy such as hydrocortisone. 
 
5.2.5 Immune-Related Adverse Events (irAEs)Reactions and Immune-
mediated Adverse Reactions: Definition, Monitoring, and Treatment 
Blocking CTLA-4 and PD-1 function may permit the emergence of auto-reactive T cells 
and resultant clinical autoimmunity. Rash/vitiligo, diarrhea/colitis, uveitis/episcleritis, 
hepatitis, and hypopituitarism were drug-related, presumptive autoimmune events, now 
termed immune-mediated adverse reactions, noted in previous ipilimumab studies. 
For the purposes of this study, an immune-related adverse reaction is defined as an adverse 
reaction of unknown etiology associated with drug exposure and consistent with an 
immune phenomenon. Efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin or other etiologic causes prior to labeling an event an immune-related adverse 
reactions. Serologic, immunologic, and histologic (biopsy) data should be used to support 
the diagnosis of an immune-related toxicity. Suspected immune-related adverse reactions 
must be documented on an AE or SAE form. Another term for an irAE is an immune-
mediate adverse reaction, as it is termed in the Ipilimumab US Prescribing Information. 
Both terms may be used in this protocol document.  
Patients should be informed of and carefully monitored for evidence of clinically 
significant systemic immune-mediated adverse reactions (e.g., systemic lupus 
erythematosus-like diseases) or organ-specific immune-mediated adverse reaction (e.g., 
rash, colitis, uveitis, hepatitis or thyroid disease). If an immune-mediated adverse reaction 
is noted, appropriate work-up (including biopsy if possible) should be performed, and 
steroid therapy may be considered if clinically necessary.   
It is unknown if systemic corticosteroid therapy has an attenuating effect on ipilimumab 
activity. However, clinical anti-tumor responses have been maintained in patients treated 
with corticosteroids and discontinued from ipilimumab. If utilized, corticosteroid therapy 

 
 
56 
should be individualized for each patient. Prior experience suggests that colitis manifested 
as ≥ Grade 3 diarrhea requires corticosteroid treatment. 
Specific treatment algorithms for immune-mediated adverse reactions adverse events are 
included as appendices B. 
5.2.6 Other Guidance 
Treatment of Nivolumab or Ipilimumab Related Infusion Reactions Since nivolumab and 
ipilimumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, 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 mild symptoms, Grade 1 (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 administrations.For 
moderate symptoms, Grade 2  
 (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, then 
restart the infusion at 50% of the original infusion rate when symptoms resolve; if no 
further complications ensue after 30 minutes, the rate may be increased to 100% of the 
original infusion rate. Monitor subject closely. If symptoms recur then no further 
nivolumab or ipilimumab will be administered at that visit. Administer 
diphenhydramine 50 mg IV, and remain at bedside and monitor the subject until 
resolution of symptoms. The amount of study drug infused must be recorded on the 
electronic case report form (eCRF). 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 

 
 
57 
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 severe symptoms, Grade 3 or Grade 4  
(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 ventilator 
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). 
5.2.6.a Treatment of Nivolumab or  Ipilimumab-Related Isolated Drug Fever 
In the event of isolated drug fever, the investigator must use clinical judgment to determine 
if the fever is related to the ipilimumab or to an infectious etiology. If a patient experiences 
isolated drug fever, for the next dose, pre-treatment with acetaminophen or non-steroidal 
anti-inflammatory agent (investigator discretion) should be instituted and a repeated 
antipyretic dose at 6 and 12 hours after ipilimumab infusion, should be administered. The 
infusion rate will remain unchanged for future doses. If a patient experiences recurrent 
isolated drug fever following premedication and post dosing with an appropriate 
antipyretic, the infusion rate for subsequent dosing should be decreased to 50% of the 
previous rate. If fever recurs following infusion rate change, the investigator should assess 
the patient’s level of discomfort with the event and use clinical judgment to determine if 
the patient should receive further ipilimumab. 
5.2.6.b Monitoring and Management of Immune-mediated Adverse 
Reactions 
Refer to Appendix B for algorithms recommended for utilization in CA184-187. 

 
 
58 
5.2.6.c Liver Function Test (LFT) Assessments Required Before 
Administration of Nivolumab or Ipilimumab 
Liver function tests (AST, ALT, T. bilirubin) will be evaluated for every subject prior to 
administration of nivolumab or ipilimumab. Blood samples must be collected and analyzed 
at local or central labs within 7 days prior to dosing. LFT results must be reviewed by the 
principal investigator (or designee) to meet dosing criteria specifications:  2.5 x ULN for 
AST, ALT and  2 x ULN for T. bilirubin unless liver metastases are present in which case 
LFT  5 x ULN for AST, ALT and T. bilirubin  3.0 x ULN) prior to dosing.  
If, during the course of treatment abnormal LFT values are detected, the subject must be 
managed using the hepatotoxicity algorithm section in Appendix B. 
5.3 Prohibited and Restricted Therapies During the Study 
5.3.1 Prohibited Therapies 
Patients in this study may not use vaccines for the treatment of cancer or prevention of 
disease unless indicated as a component of the protocol regimen (including those for 
common medical conditions) for up to one month pre and post dosing with ipilimumab. 
Concomitant systemic or local anti-cancer medications or treatments are prohibited in this 
study while receiving ipilimumab treatments.  
Patients may not use any of the following therapies during the study: 
 Any non-study anti-cancer agent (investigational or non-investigational) 
 Any other investigational agents 
 Any other (non-CA184024 related) CTLA-4 inhibitors or agonists 
 Immunosuppressive agents 
 Chronic systemic corticosteroids 
 Any non-oncology vaccine therapies used for the prevention of infectious diseases (for 
up to 30 days prior to or after any dose of study drug). 
5.3.2 Restricted Therapies 
Not applicable. 
5.3.3 Precautions 
Caution is advised when considering treatment with high-dose IL-2 in patients who have 
previously been administered ipilimumab, particularly in patients who experienced 
ipilimumab-related diarrhea/colitis. Colonoscopy or sigmoidoscopy with biopsy may be 
advisable prior to IL-2 administration once the patient is no longer receiving ipilimumab. 

 
 
 
59 
 
6 STUDY PROCEDURES AND OBSERVATIONS 
6.1 Time and Events Schedule  
Table 10:  Time and Events Schedule for Protocol 
Procedure 
Baselinea 
Week  
1, 4, 7, 10 
Week  
13 and 
every 4 
weeks 
thereafter 
Week 13 
and every 
12 weeks 
thereafter 
End of 
Study 
Eligibility 
 
 
 
 
 
Consent 
x 
 
 
 
 
Inclusion/Exclusion    
x 
 
 
 
 
Medical History 
x 
 
 
 
 
Safety Assessments 
 
 
 
 
 
Interim History 
x 
x 
x 
 
x 
Physical Examination 
x 
x 
x 
 
x 
Vital signs, Heightc, 
Weight, Performance 
Status 
xc 
x 
x 
 
x 
Adverse Events 
x 
x 
xb 
 
x 
Concomitant 
Medications 
x 
x 
x 
 
x 
Common Laboratory 
Tests 
x 
x 
xb 
 
x 

 
 
 
60 
 
Liver Function Tests 
x 
x 
xb 
 
x 
Thyroid Function 
Tests 
x 
x 
 
x 
x 
Pregnancy Teste 
x 
x 
 
 
 
Tumor 
Measurementsc 
x 
 
 
x 
 
Correlative studiesd 
 
x 
x 
 
x 
Nivolumab infusion 
 
x 
xb 
 
 
Ipilimumab infusion 
 
x 
 
 
 
 
a. Baseline visit and Week 1 visit may occur simultaneously.  
b. 
Patients will have adverse event assessments, common laboratory tests, liver function tests, and treatment every 4 weeks thereafter until removed from 
study. 
c. 
Tumor assessments will occur at baseline, Week 13 and every 12 weeks thereafter until removed from study.  Assessments will have a window of +/- 7 
days and will be in the form of CT chest, abdomen, pelvis with oral and intravenous contrast or acceptable alternative body imaging at the discretion of 
the investigator.  Brain imaging only at the discretion of the investigator. 
d. 
Mandatory biopsy one-time during induction weeks 4-12, optional biopsy during maintenance and at the end of study 
e. 
Pregnancy test will be every 4 weeks during Maintenance phase (every other visit). 
 
 

 
 
 
61 
6.2 Procedures by Visit 
The Time and Events Schedule summarizes the frequency and timing of various 
measurements. 
6.2.1 Study Procedures by Visit and Treatment Cycle 
Note that results of all safety laboratory tests (that is, all chemistry and all hematology 
results) must be obtained and reviewed by the investigator or his designee before each 
ipilimumab administration.  All induction period laboratory samples must be collected 
within a window of up to 7 days before administration of nivolumab or ipilimumab. The 
order set for infusion will require labs to be verified prior to administration.  Hold and 
notify MD parameters will be given on the order set.   
6.2.1.a  Screening/Baseline Visit 
Eligible patients will have a screening/baseline visit that may, in some instances, occur 
simultaneously with Treatment Visit 1.  During this visit, the patient will have: a review of 
his/her medical history; physical examination including vital signs; assessment of signs, 
symptoms, concomitant medications, and adverse events; a review of common laboratory 
tests (CBC with differential, basic metabolic panel), a pregnancy test (within 72 hours of 
first dose) if applicable, liver function test (AST, ALT, T. bilirubin), and thyroid function 
test (TSH, free T4).  In addition, study personnel will review inclusion/exclusion criteria, 
tumor assessments, and review and sign the informed consent document with the patient. 
All screening evaluations with the exception of pregnancy test should be completed within 
28 days (+/- 7 days) of start of protocol treatment. 
6.2.1.b Treatment Visits 
At each treatment visit during the induction phase, the patient will have a physical 
examination including vital signs, assessment of signs, symptoms, and adverse events, 
review of laboratory data and a concomitant medication assessment. If the Baseline Visit 
occurs within 14 days of Treatment Visit 1, physical examination can be omitted from 
Treatment Visit 1.  During the maintenance phase, patients will have adverse event 
assessment and treatment every 4 weeks, and physical examination including vital signs 
every 4 weeks. 

 
 
 
62 
6.2.2 Tissue Biopsies for Immune Biomarker Studies 
During the induction phase, patients will have mandatory biopsy of tumor tissue for 
exploratory studies. This biopsy can occur any time after cycle 1 until the end of cycle 4 
(weeks 4-12). 
During the maintenance phase and at the end of study, patients have the option to undergo 
an additional biopsy of tumor tissue for exploratory biomarker studies. 
6.2.3 Exploratory Correlative Studies 
Tissues collected for exploratory correlates may be analyzed for immunological features 
using platforms included, but no limited to immunohistochemistry (IHC) for T cells (CD3, 
CD4, CD8, CD68). Molecular analytes (e.g. DNA, m RNA, protein) may be extracted as 
available tissue allows and characterized using a variety of analytic platforms, or the most 
efficacious method for a particular analyte at the time of analysis including whole 
transcriptomic profiling, RNASeg, Nanostring, Reverse Phase Protein Array, and next 
generation sequencing. 
6.2.4 Study Completion or Early Discontinuation Visit 
At the time of study early withdrawal, the reason for early withdrawal and any new or 
continuing adverse events should be documented. A concomitant medication assessment 
will also be performed. 
6.2.5 Study Drug Discontinuation 
If study drug administration is discontinued, the reason for discontinuation will be 
recorded. 
6.3 Details of Procedures 
6.3.1 Study Materials 
Bristol-Myers Squibb (BMS) will provide nivolumab and ipilimumab at no cost for this 
study. 
6.3.2 Safety Assessments 
All patients who receive at least one dose of treatment will be considered evaluable for 
safety parameters. Additionally, any occurrence of non-SAE or SAE from time of consent 
forward, up to and including follow-up visits, will be reported. See Section 8: Adverse 
Event Reporting. 

 
 
 
63 
6.4 Criteria for Evaluation 
6.4.1 Safety Evaluation 
Safety will be evaluated for all treated patients using the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 
(http://ctep.cancer.gov). Safety assessments will be based on medical review of adverse 
event reports and the results of vital sign measurements, physical examinations, and 
clinical laboratory tests. 
6.4.2 Efficacy Evaluation 
All efficacy evaluations will be conducted by the investigator or their designee using the 
response criteria established by the World Health Organization (WHO). All subject’s 
results will documented in the subject’s eCRF. 
6.4.2.a Definition of Measurable and Non-Measurable Lesions 
 Measurable Lesions are lesions that can be accurately measured in two perpendicular 
diameters, with at least one diameter ≥ 20 mm and the other dimension ≥ 10 mm (10 
mm x 10 mm for spiral CT). The area will be defined as the product of the largest 
diameter with its perpendicular. Skin lesions can be considered measurable. 
 Non-Measurable 
(evaluable) 
Lesions 
are 
all 
other 
lesions, 
including 
unidimensionally measurable disease and small lesions (lesions without at least one 
diameter ≥ 20 mm), and any of the following: 
 Lesions occurring in a previously irradiated area (unless they are documented as 
new lesions since the completion of radiation therapy), bone lesions, 
leptomeningeal disease, ascites, pleural or pericardial effusion, lymphangitis 
cutis/pulmonis, abdominal masses that are not pathologically/cytologically 
confirmed and followed by imaging techniques and cystic lesions. 
 All measurable and non-measurable lesions should be measured at screening and 
at the defined tumor assessment timepoints (see Section 5, Table 2). Extra 
assessments may be performed, as clinically indicated, if there is a suspicion of 
progression. 
6.4.2.b Definition of Index/Non-Index Lesions 
All measurable lesions, up to a maximum of five lesions per organ and ten lesions in 
total, should be identified as index lesions to be measured and recorded on the medical 
record at Screening. The index lesions should be representative of all involved organs. In 
addition, index lesions should be selected based on their size (lesions with the longest 
diameters), their suitability for accurate repeat assessment by imaging techniques, and how 

 
 
 
64 
representative they are of the patient’s tumor burden. At Screening, a sum of the products 
of diameters (SPD) for all index lesions will be calculated and considered the baseline sum 
of the products of diameters. Response criteria to be followed are listed below. The baseline 
sum will be used as the reference point to determine the objective tumor response of the 
index lesions at tumor assessment (TA). 
Measurable lesions, other than index lesions, and all sites of non-measurable disease, will 
be identified as non-index lesions. Non-index lesions will be recorded on the medical record 
and should be evaluated at the same assessment time points as the index lesions. In 
subsequent assessments, non-index lesions will be recorded as “stable or decreased 
disease,” “absent,” or “progression.” 
6.4.3 Definition of Tumor Response Using irRC 
The sum of the products of diameters at tumor assessment using the immune-related 
response criteria (irRC) for progressive disease incorporates the contribution of new 
measurable lesions. Each net Percentage Change in Tumor Burden per assessment using 
irRC criteria accounts for the size and growth kinetics of both old and new lesions as they 
appear. 
6.4.3.a Definition of Index Lesions Response Using irRC 
 irComplete Response (irCR): Complete disappearance of all index lesions. This 
category encompasses exactly the same subjects as “CR” by the mWHO criteria. 
 irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater in the sum 
of the products of the two largest perpendicular diameters of all index and all new 
measurable lesions (ie., Percentage Change in Tumor Burden). Note: the appearance of 
new measurable lesions is factored into the overall tumor burden, but does not 
automatically qualify as progressive disease until the SPD increases by ≥25% when 
compared to SPD at nadir. 
 irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the absence of 
progressive disease. 
 irProgressive Disease (irPD): At least 25% increase Percentage Change in Tumor 
Burden (i.e., taking sum of the products of all index lesions and any new lesions) when 
compared to SPD at nadir. 
6.4.3.b Definition of Non-Index Lesions Response Using irRC 
 irComplete Response (irCR): Complete disappearance of all non-index lesions. This 
category encompasses exactly the same subjects as “CR” by the mWHO criteria. 
 irPartial Response (irPR) or irStable Disease (irSD): non-index lesion(s) are not 
considered in the definition of PR, these terms do not apply. 

 
 
 
65 
 
irProgressive Disease (irPD): Increases in number or size of non-index lesion(s) does 
not constitute progressive disease unless/until the Percentage Change in Tumor Burden 
increases by 25% (i.e., the SPD at nadir of the index lesions increases by the required 
amount). 
6.4.3.c Impact of New Lesions on irRC 
New lesions in and by themselves do not qualify as progressive disease. However their 
contribution to total tumor burden is included in the SPD which in turn feeds into the irRC 
criteria for tumor response. Therefore, new non-measurable lesions will not discontinue 
any subject from the study. 
6.4.3.d Definition of Overall Response Using irRC 
Overall response using irRC will be based on these criteria: 
 Immune-Related Complete Response (irCR): Complete disappearance of all tumor 
lesions (index and nonindex together with no new measurable/unmeasurable lesions) 
for at least 4 weeks from the date of documentation of complete response.  
 Immune-Related Partial Response (irPR): The sum of the products of the two largest 
perpendicular diameters of all index lesions is measured and captured as the SPD 
baseline. At each subsequent tumor assessment, the sum of the products of the two 
largest perpendicular diameters of all index lesions and of new measurable lesions are 
added together to provide the Immune Response Sum of Product Diameters (irSPD). 
A decrease, relative to baseline of the irSPD compared to the previous SPD baseline, 
of 50% or greater is considered an immune Partial Response (irPR).  
 Immune-Related Stable Disease (irSD): irSD is defined as the failure to meet criteria 
for immune complete response or immune partial response, in the absence of 
progressive disease.  
 Immune-Related Progressive Disease (irPD): It is recommended in difficult cases to 
confirm PD by serial imaging. Any of the following will constitute progressive disease: 
 At least 25% increase in the sum of the products of all index lesions over baseline 
SPD calculated for the index lesions. 
 At least a 25% increase in the sum of the products of all index lesions and new 
measurable lesions (irSPD) over the baseline SPD calculated for the index lesions. 

 
 
 
66 
Table 11: Immune-Related Response Criteria Definitions 
Index 
Lesion 
Definition 
Non-Index 
Lesion 
Definition 
New 
Measurable 
Lesions 
New 
Unmeasurable 
Lesions 
Percent change in 
tumor burden 
(including measurable 
new lesions when 
present) 
Overall 
irRC 
Response 
Complete 
Response 
Complete 
Response 
No 
No 
-100% 
irCR 
Partial 
Response 
Any 
Any 
Any 
> -50% 
irPR 
<-50% to <+25% 
irSD 
>+25% 
irPD 
Stable 
Disease 
Any 
Any 
Any 
<-50% to <+25% 
irSD 
>+25% 
irPD 
Progressive 
Disease 
Any 
Any 
Any 
>+25% 
irPD 
 
6.4.3.e Immune-Related Best Overall Response Using irRC (irBOR)  
irBOR is the best confirmed irRC overall response over the study as a whole, recorded 
between the date of first dose until the last tumor assessment before subsequent therapy 
(except for local palliative radiotherapy for painful bone lesions) for the individual subject 
in the study. For the assessment of irBOR, all available assessments per subject are 
considered. 
irCR or irPR determinations included in the irBOR assessment must be confirmed by a 
second (confirmatory) evaluation meeting the criteria for response and performed no less 
than 4 weeks after the criteria for response are first met. 
For metastatic patients, imaging of the chest, abdomen and pelvis is required at screening 
(ie, baseline) and at each tumor assessment visit, regardless of the location of known 
metastases. Refer to Section 6.1 Time and Events Schedule for further information.  Similar 
methods of tumor assessment and similar techniques must be used to characterize each 
identified and reported lesion at screening and during subsequent tumor assessments. 
Imaging-based evaluation is preferred to clinical examination.  For adjuvant patients, 
imaging of the chest, abdomen and pelvis is required at baseline and at Week 24 (+/- 7 
days) and every 6 months thereafter (+/- 7 days) until removal from or completion of study. 

 
 
 
67 
6.4.4 Response Endpoints 
Nivolumab and ipilimumab are expected to trigger immune-mediated responses, which 
require activation of the immune system prior to the observation of clinical responses. Such 
immune activation may take weeks to months to be evident. Some patients may have 
objective volume increase of tumor lesions or other disease parameters (based on study 
indication, ie, hematologic malignancies) within 12 weeks following the start of 
ipilimumab dosing. Such patients may not have had sufficient time to develop the required 
immune activation or, in some patients, tumor volume or other disease parameter increases 
may represent infiltration of lymphocytes into the original tumor or blood. In conventional 
studies, such tumor volume or relevant laboratory parameter increases during the first 12 
weeks of the study would constitute PD and lead to discontinuation of imaging to detect 
response, thus disregarding the potential for subsequent immune-mediated clinical 
response.  
Therefore, patients with tumor volume increase detected or lack of laboratory parameter 
response documentation prior to week 12 but without rapid clinical deterioration should 
continue to be treated and clinically observed with a stringent imaging schedule to allow 
detection of a subsequent tumor response. This will improve the overall assessment of the 
clinical activity or ipilimumab and more likely capture its true potential to induce clinical 
responses. Tumor assessments will be made using modified WHO criteria. 
7 INVESTIGATIONAL PRODUCT 
The investigational product is defined as a pharmaceutical form of an active ingredient 
being tested as a reference in the study,. In this study, the investigational products are 
nivolumab and ipilimumab. 
Other medications used in the study as support or escape medication for preventative, 
diagnostic, or therapeutic reasons, as components of the standard of care for a given 
diagnosis, are considered noninvestigational products. In this protocol, noninvestigational 
product(s) is/are: acetaminophen, diphenhydramine, hydroxyzine, anti-emetics including 
but not limited to ondansetron, promethazine, prochlorperazine, and corticosteroids.  
7.1 Identification 
 
Product Description: Treatment Period 

 
 
 
68 
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 
Injection(a) 
100 mg (10 
mg/mL) 
10 mL 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 form 
light and 
freezing 
 
Ipilimumab 
Solution for 
Injection 
50 mg/10 
mL and 
200 mg/40 
mL (5 
mg/mL) 
40 mL 
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 
7.2 Packaging and Labeling 
BMS will provide drugs at no cost for this study. Nivolumab and ipilimumab will be 
provided in open-label containers. The labels will contain the protocol prefix, batch 
number, content, storage conditions, and dispensing instructions along with the 
Investigational New Drug (IND) caution statement. 
7.3 Storage, Handling, and Dispensing 
7.3.1 Storage 
Both drugs must be stored in a secure area according to local regulations. The investigator 
must ensure that they are stored at a temperature  2C and  8C. 

 
 
 
69 
7.3.2 Handling and Disposal 
As with all injectable drugs, care should be taken when handling and preparing nivolumab 
or ipilimumab. Whenever possible, nivolumab or ipilimumab should be prepared in a 
laminar flow hood or safety cabinet using standard precautions for the safe handling of 
intravenous agents applying aseptic technique. Latex gloves are required. If drug 
concentrate or solution comes in contact with skin or mucosa, immediately and thoroughly 
wash with soap and water. After final drug reconciliation, unused drug solution should be 
disposed at the site following procedures for the disposal of anticancer drugs.   
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. 
7.3.3 Dispensing 
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. 
7.4 Drug Ordering and Accountability 
7.4.1 Initial Orders 
Following submission and approval of the required regulatory documents, drug supply may 
be ordered from BMS. Investigators must complete a Drug Request Form. This order form 
will be provided by the BMS protocol manager. 
 
Ipilimumab vials (40 mL) are shipped in quantities of five. The initial order should be 
limited to 25 vials (5 cartons of 5 vials each). Allow 5 business days for shipment of drug 
from BMS receipt of the Drug Request Form. Drug is protocol specific, but not patient 
specific. All product will be shipped via Federal Express in a temperature-controlled 
container. Shipments will be made from Fisher Clinical Services on Monday through 
Thursday for delivery onsite Tuesday through Friday. There will be no weekend or holiday 
delivery of drugs. 
It is possible that sites may have more than one nivolumab and/or ipilimumab clinical study 
ongoing at the same time. It is imperative that only product designated for this protocol 
number be used for this study. To help segregate product for this study from other 

 
 
 
70 
investigational or marketed product, stickers bearing the BMS protocol number will be 
provided and should be affixed to the front of the outer carton just above the company 
names so as not to obscure any marking. 
7.4.2 Re-Supply 
Reorders 
should 
be 
emailed 
directly 
to 
Fisher 
Clinical 
Services 
(distribution.allentown@thermofisher.com) for shipment within 5 business days. When 
assessing need for resupply, institutions should keep in mind the number of vials used per 
treatment dose, and that shipments may take 5 business days from BMS receipt of request. 
Drug is not patient specific. Be sure to check with your pharmacy regarding existing 
investigational stock to assure optimal use of drug on hand. 
7.5 Investigational Product Accountability 
It is the responsibility of the investigator to ensure that a current record of investigational 
product disposition is maintained at each study site where investigational product is 
inventoried and disposed. Records or logs must comply with applicable regulations and 
guidelines, and should include: 
 Amount received and placed in storage area. 
 Amount currently in storage area. 
 Label ID number or batch number and use date or expiry date. 
 Dates and initials of person responsible for each ipilimumab inventory 
entry/movement. 
 Amount dispensed to and returned by each subject, including unique subject identifiers. 
 Amount transferred to another area/site for dispensing or storage. 
 Non-study disposition (e.g., lost, wasted, broken). 
 Amount destroyed at study site. 
7.6 Investigational Product Destruction 
If investigational product is to be destroyed on site, it is the investigator’s responsibility 
to ensure that arrangements have been made for disposal and that procedures for proper 
disposal have been established according to applicable regulations, guidelines, and 
institutional procedures. BMS agrees to drug disposal and destruction per MDACC 
institutional policy. Appropriate records of the disposal must be maintained. 

 
 
 
71 
8 ADVERSE EVENT REPORTING 
8.1 Collection of Safety Information 
Adverse events will be documented in the medical record and entered into PDMS/CORe 
according to the following guidelines… 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening 
of a pre-existing medical condition in a patient or 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 (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of investigational product, whether or not 
considered related to the investigational product. Any Adverse Events considered common 
for this disease process (uveal melanoma, metastatic uveal melanoma) or related to disease 
will be captured at the discretion of the attending MD. 
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.) 
8.1.1 Definition of Serious Adverse Events 
A serious AE (SAE) is any untoward medical occurrence that at any dose:  
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
 Death 
 A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it occurred 
in a more severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 

 
 
 
72 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse 
(21 CFR 312.32). 
 Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
 All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB and BMS in accordance with the timeframes and procedures 
outlined in “The University of Texas M. D. Anderson Cancer Center Institutional Review 
Board Policy for Investigators on Reporting Unanticipated Adverse Events for Drugs and 
Devices”. Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must 
be reported to the IND Office, regardless of attribution (within 5 working days of 
knowledge of the event). 
 
8.1.2 Definition of Nonserious Adverse Event 
A nonserious adverse event is an AE not classified as serious. 
8.2 Assignment of Adverse Event Intensity and Relationship to 
Investigational Product 
The following categories and definitions of causal relationship to investigational product 
as determined by a physician should be used: 
 Related: There is a reasonable causal relationship to investigational product 
administration and the adverse event. 
 Not Related: There is not a reasonable causal relationship to investigational product 
administration and the adverse event. 
The expression “reasonable causal relationship” is meant to convey in general that there 
are facts (eg, evidence such as de-challenge/re-challenge) or other arguments to suggest a 
positive causal relationship. 
8.3 Collection and Reporting 
 All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge 
of the event to the Safety Project Manager in the IND Office.   
 Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB.  

 
 
 
73 
 Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 100 days after the last dose of drug, unless the participant 
withdraws consent. Serious adverse events must be followed until clinical recovery is 
complete and laboratory tests have returned to baseline, progression of the event has 
stabilized, or there has been acceptable resolution of the event. 
 Additionally, any serious adverse events that occur after the 100 day time period that 
are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy. 
Reporting to FDA: 
 Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional Review 
Board policy. 
Investigator Communication with Supporting Companies: 
All events occurring during the conduct of a protocol and meeting the definition of a 
SAE must be reported to the IRB and BMS in accordance with the timeframes and 
procedures outlined in “The University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy for Investigators on Reporting Unanticipated 
Adverse Events for Drugs and Devices”.  Unless stated otherwise in the protocol, all 
SAEs, expected or unexpected, must be reported to the IND Office, regardless of 
attribution (within 5 working days of knowledge of the event). 
 
8.3.1 Serious Adverse Events 
Following the subject’s written consent to participate in the study, all SAEs must be 
collected, including those thought to be associated with protocol-specified procedures. All 
SAEs must be collected that occur within 100 days of discontinuation of dosing of the 
investigational product. If applicable, SAEs must be collected that relate to any later 
protocol-specified procedure (eg, a follow-up skin biopsy). The investigator should notify 
BMS of any SAE occurring after this time period that is believed to be related to the 
investigational product or protocol-specified procedure. 
All SAEs whether related or unrelated to the ipilimumab, must be immediately reported to 
BMS (by the investigator or designee) within 24 hours of becoming aware of the event. If 

 
 
 
74 
only limited information is initially available, follow-up reports are required. The original 
SAE form must be kept on file at the study site. 
All SAEs should be faxed or emailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
For studies conducted under an Investigator IND, any event that is both serious and 
unexpected must be reported to the FDA as soon as possible and, in no event, later than 7 
days (death or life-threatening event) or 15 days (all other SAEs) after the investigator’s 
or institution’s initial receipt of the information. BMS will be provided with a 
simultaneous copy of all adverse events filed with the FDA. The MDACC “Internal SAE 
Report Form for Prompt Reporting” will be used for reporting to the IRB Office and to 
BMS. 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
Serious adverse events, whether related or unrelated to investigational product, must be 
recorded on the SAE page and reported expeditiously to BMS (or designee) to comply with 
regulatory requirements. An SAE report should be completed for any event where doubt 
exists regarding its status of seriousness.  
All SAEs must be immediately reported by confirmed facsimile transmission (fax) and 
mailing of the completed SAE page. In some instances where a facsimile machine is not 
available, overnight express mail may be used. 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.) In selected circumstances, the protocol may 
specify conditions that require additional telephone reporting.  
If the investigator believes that an SAE is not related to the investigational product, 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 page. 
If an ongoing SAE changes in its intensity or relationship to the investigational product, a 
follow-up SAE report should be sent immediately to the sponsor. As follow-up information 

 
 
 
75 
becomes available it should be sent immediately using the same procedure used for 
transmitting the initial SAE report. All SAEs should be followed to resolution or 
stabilization.  
  The adverse events will be recorded in PDMS according to the following guidelines. The 
Investigator or physician designee is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for each event for all 
subjects enrolled on the trial. 
 
Recommended Adverse Event Recording Guidelines  
Attribution 
Grade 1 Grade 2 
Grade 3 
Grade 4 Grade 5 
  
  
  
    
  
Unrelated 
Phase I 
Phase I 
Phase I     
Phase II     
Phase I     
Phase II  
Phase 
III 
Phase I     
Phase II  
Phase 
III 
Unlikely 
Phase I 
Phase I 
Phase I     
Phase II     
Phase I     
Phase II  
Phase 
III 
Phase I     
Phase II  
Phase 
III 
Possible 
Phase I     
Phase II 
Phase I     
Phase II  
Phase 
III 
Phase I     
Phase II  
Phase 
III 
  
Phase I     
Phase II  
Phase 
III 
Phase I     
Phase II  
Phase 
III 
Probable 
Phase I     
Phase II 
Phase I     
Phase II  
Phase 
III 
Phase I     
Phase II  
Phase 
III 
  
Phase I     
Phase II  
Phase 
III 
Phase I     
Phase II  
Phase 
III 
Definitive 
Phase I     
Phase II 
Phase I     
Phase II  
Phase 
III 
Phase I     
Phase II  
Phase 
III 
  
Phase I     
Phase II  
Phase 
III 
Phase I     
Phase II  
Phase 
III 
 
 
8.3.2 Reporting to FDA 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Project Manager, 
IND office) according to 21 CFR 312.32. 
 

 
 
 
76 
8.3.3 Handling of Expedited Safety Reports 
In accordance with local regulations, BMS will notify investigators of all SAEs that are 
suspected (related to the investigational product) and unexpected (ie, not previously 
described in the Investigator Brochure). In the European Union (EU), an event meeting 
these criteria is termed a Suspected, Unexpected Serious Adverse Reaction (SUSAR). 
Investigator notification of these events will be in the form of an expedited safety report 
(ESR).  
  
In addition, suspected serious adverse reactions (whether expected or unexpected) shall be 
reported by local IRB to the relevant competent health authorities in all concerned countries 
according to local regulations (either as expedited and/or in aggregate reports). 
8.3.4 Nonserious Adverse Events 
The collection of nonserious AE information should begin at initiation of investigational 
product. If an ongoing nonserious AE worsens in its intensity, or if its relationship to the 
investigational product changes, a new nonserious AE entry for the event should be 
completed. Nonserious AEs should be followed to resolution or stabilization, or reported 
as SAEs if they become serious. Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of investigational product, or those that are present at the 
end of study participation. Subjects with nonserious AEs at study completion should 
receive post-treatment follow-up as appropriate. 
All identified nonserious AEs must be recorded and described in the medical record. 
8.3.5 Pregnancy 
Sexually active WOCBP must use an effective method of birth control during the course 
of the study, in a manner such that risk of failure is minimized. Before enrolling WOCBP 
in this clinical study, the investigator must review the guideline about study participation 
for WOCBP which can be found in the GCP Manual for Investigators. The topics include 
the following: 
 General Information 
 Informed Consent Form 
 Pregnancy Prevention Information Sheet 
 Drug Interactions with Hormonal Contraceptives 
 Contraceptives in Current Use 

 
 
 
77 
 Guidelines for the Follow-up of a Reported Pregnancy. 
Before study enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during study participation and the potential risk factors for an unintentional 
pregnancy. The subject must sign an informed consent form documenting this discussion. 
All WOCBP MUST have a negative pregnancy test within 72 hours before receiving 
ipilimumab. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent 
units of HCG. If the pregnancy test is positive, the subject must not receive ipilimumab 
and must not be enrolled in the study. 
Women of childbearing potential (WOCBP) and fertile men with partners of childbearing 
potential must be using an adequate method of contraception to avoid pregnancy 
throughout the study and for up to 26 weeks after the last dose of investigational product. 
In addition, all WOCBP should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (e.g., missed or late menstrual period) at any 
time during study participation. 
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 investigational product 
exposure, including during at least 6 half-lives after product administration, the 
investigational product will be permanently discontinued in an appropriate manner (eg, 
dose tapering if necessary for subject safety). The investigator must immediately notify 
BMS of this event and record the pregnancy on the Pregnancy Surveillance Form (not an 
SAE form). Initial information on a pregnancy must be reported immediately to BMS, and 
the outcome information provided once the outcome is known. Completed Pregnancy 
Surveillance Forms must be forwarded to BMS according to SAE reporting procedures. 
Any pregnancy that occurs in a female partner of a male study participant should be 
reported to the sponsor. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form. 
Protocol-required procedures for study discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. In addition, the 
investigator must report to BMS, and follow-up on information regarding the course of the 
pregnancy, including perinatal and neonatal outcome. Infants should be followed for a 
minimum of 8 weeks. 

 
 
 
78 
8.3.6 Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not 
these procedures are required by the protocol, should also be recorded in the medical 
record. 
9. Statistical Methodology 
 
The trial originally used Simon’s two-stage design to target a response rate of 15% vs. a 
historical rate of 5%.  A total of 30 patients were to have been enrolled in the first stage, 
and if at least two had responded, an additional 22 patients would have been enrolled in 
the second stage.  Given advancements in melanoma treatment, a 15% response rate is no 
longer considered interesting, and in 2017, the study has been changed to a single-stage 
design targeting a response rate of 20%.  A total of 23 evaluable patients have been 
enrolled at the time of this change. 
 
 
A single-stage trial design will be employed to enroll patients on the metastatic arm with 
the following assumptions: 
 Type I error rate of 5%, power of 80% 
 Null hypothesis of 5% response rate 
 Alternate hypothesis of 20% response rate 
 Response will be defined as those patients who achieve RECIST CR + PR.   
 Accounting for attrition (inevaluable patients, 25%) and screen fails (5%), up to 39 
patients are needed to achieve a target enrollment of 27 evaluable patients.  
 If at least 4 of the 27 patients are responders, the null hypothesis of a 5% response 
rate will be rejected in favor of the alternative hypothesis. 
If the true probability of response if 5%, this design has a 4.4% chance of incorrectly 
concluding that it is effective. If the true probability of response is 20%, the design has an 
18.2 % chance of incorrectly concluding that it is not effective. 

 
 
 
79 
 
Safety Analysis at baseline, a medical history will be obtained to capture relevant 
underlying conditions. The baseline examinations should include weight, height, ECOG 
Performance Status, BP, HR, temperature and oxygen saturation by pulse oximetry at rest 
and after exertion and should be performed as noted in Table 10 Notes Baseline signs and 
symptoms are those that are assessed within 14 days prior to randomization. Concomitant 
medications will be collected from within 14 days prior to randomization through the study 
treatment period.  
 
Baseline local laboratory assessments should be done within 14 days prior to treatment to 
include: CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN 
or serum urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, lipase, TSH, 
Free T4, Free T3, and Hep B and C testing only as clinically indicated (HBV sAg, HCV 
Ab or HCV RNA). Pregnancy testing for WOCBP (done locally) must be performed within 
24 hours prior to the initial administration of study drug at baseline and then within 24 
hours of dosing at Week 1 and Week 4 of cycle 1 and , 3  and Week 1 and Week 5 starting 
from cycle 5 and at the safety follow up visits. 
 
Subjects will be evaluated for safety if they have received any study drug. Toxicity 
assessments will be continuous during the treatment phase. During the safety follow-up 
phase, toxicity assessments should be done in person. Once subjects reach the survival 
follow-up phase either in person or documented telephone calls to assess the subject’s 
status are acceptable.  
 
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 
4.0.  
On-study weight and ECOG Performance status should be assessed on Day 1 of Weeks 1, 
3, 4 and 5 during cycles 1 and 2 (except Cycle 1 Day 1) and Day 1 of Weeks 1, 3 and 5 
starting from Cycle 3 and vital signs should be assessed at each on-study visit (except Cycle 
1 Day 1). 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 and after exertion 
should be assessed at each on-study visit prior to dosing. The start and stop time of the 

 
 
 
80 
nivolumab 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. 
 
On study local laboratory assessments should be done within 72 hours of dosing to include; 
CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or 
serum urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, lipase, TSH with 
Free T4, Free T3 on Day 1 of Weeks 1, 4, 7, 10 and 13, then every 12 weeks. 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 dosing and at any 
time a subject has any new or worsening respiratory symptoms. A reading at rest and on 
exertion should be obtained at each time point. The extent of the exertion should be based 
on the judgment of the investigator, but should remain consistent for each individual 
subject throughout the study. If the patient’s subject’s status changes, the investigator can 
alter the extent of exertion based on their medical judgment. If a subject shows changes on 
pulse oximetry or other pulmonary related signs (hypoxia, fever) or symptoms (eg, 
dyspnea, cough, fever) 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 the nivolumab 
Investigator’s Brochure. 
 
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.   
 

 
 
 
81 
9.1 Efficacy Analysis 
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 randomization 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 12 weeks (+/ 1 
week) from randomization and continuing every 6 weeks (+ 1 week) for the first 12 months 
from randomization and every 12 weeks (+/ 1 week) thereafter, until disease progression 
is documented or treatment is discontinued (whichever occurs later). Tumor assessments 
for ongoing study treatment decisions will be completed by the investigator using RECIST 
(Response Evaluation Criteria in Solid Tumors) 1.1 criteria.  
 
9.2 Secondary Analysis 
We will use the Kaplan-Meier method to assess the distribution of time-to-event variables, 
including overall survival, progression-free survival, and landmark analysis where 
possible.  We will use Cox proportional hazards regression methodology to model the 
association between survival parameters and clinical, disease, and demographic factors of 
interest, including data from the immune biomarker studies.   
 
10. ADMINISTRATIVE SECTION 
10.1 Compliance with the Protocol and Protocol Revisions 
The study must be conducted as described in the final approved protocol. Documentation 
of approval signed by the chairperson or designee of the IRB(s) must be sent to your BMS 
protocol manager.  
All revisions (protocol amendments, administrative letters, and changes to the informed 
consent) must be submitted to your BMS protocol manager. The investigator should not 
implement any deviation or change to the protocol without prior review and documented 
approval/favorable opinion from the IRB of an Amendment, except where necessary to 
eliminate an immediate hazard(s) to study patients. 
See also 21CFR for definitions of amendment and requirements. 

 
 
 
82 
 10.2 Informed Consent 
Investigators must ensure that subjects, or, in those situations where consent cannot be 
given by subjects, their legally acceptable representative, are clearly and fully informed 
about the purpose, potential risks, and other critical issues regarding clinical studies in 
which they volunteer to participate. Freely given written informed consent must be 
obtained from every subject or, in those situations where consent cannot be given by 
subjects, their legally acceptable representative, prior to clinical study participation, 
including informed consent for any screening procedures conducted to establish subject 
eligibility for the study. 
The rights, safety, and well-being of the study subjects are the most important 
considerations and should prevail over interests of science and society. 
 10.3 Records and Reports 
Case histories will be collected and recorded on all study patients and all data will be 
entered in the computerized Protocol Data Management System (PDMS) of the Division 
of Medicine at MD Anderson Cancer Center.  Patients must be registered in PDMS before 
a cycle of therapy can be given.  A brief explanation for required but missing data should 
be recorded as a comment.  The investigator is required to retain, in a confidential manner, 
the data pertinent to the study for the duration of the study or the maximum period required 
by applicable regulations and guidelines or institutional procedures.  If the investigator 
withdraws from the study (eg, relocation, retirement), the records shall be transferred to a 
mutually agreed upon designee (eg, another investigator or IRB).  Documentation of such 
transfer must be provided to BMS. 
 10.4 Good Clinical Practice 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined 
by the International Conference on Harmonization (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. 
 

 
 
 
83 
All potential serious breaches must be reported to BMS and to the IND Sponsor-MD 
Anderson Cancer Center (Office of Research Education and Regulatory Management) 
immediately. A serious breach is a breach of the conditions and principles of GCP in 
connection with the study or the protocol, which is likely to affect, to a significant degree, 
the safety or physical or mental integrity of the subjects of the study or the scientific 
value of the study. 
Study personnel involved in conducting this study will be qualified by education, training, 
and experience to perform their respective task(s). This study will not use the services of 
study personnel where sanctions have been invoked or where there has been scientific 
misconduct or fraud (eg, loss of medical licensure, debarment). 
Systems with procedures that ensure the quality of every aspect of the study will be 
implemented. 
 10.5 Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) 
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/process (eg, advertisements), and any other written information to be provided to 
subjects. The investigator 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 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 
10.6 Records Retention 
The investigator must retain investigational product disposition records, source documents, 
and case histories designed to record all observations and other data pertinent to the 
investigation (e.g. medical record) for the maximum period required by applicable 
regulations and guidelines, or Institution procedures. 
 
If the investigator withdraws from the study (e.g., relocation, retirement), the records shall 
be transferred to a mutually agreed upon designee (e.g., another investigator, IRB). 
Documentation of such transfer must be provided to BMS. 

 
 
 
84 
APPENDIX A: MANAGEMENT ALGORITHMS 
These general guidelines constitute guidance to the Investigator and may be 
supplemented by discussions with the Medical Monitor representing the 
Sponsor. The guidance applies to all immuno-oncology agents and regimens. 
 
A general principle is that differential diagnoses should be diligently evaluated 
according to standard medical practice. Non-inflammatory etiologies should be 
considered and appropriately treated. 
 
Corticosteroids are a primary therapy for immuno-oncology drug-related 
adverse events. The oral equivalent of the recommended IV doses may be 
considered for ambulatory patients with low-grade toxicity. The lower 
bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids. 
 
Consultation with a medical or surgical specialist, especially prior to an invasive 
diagnostic or therapeutic procedure, is recommended. 
 
The frequency and severity of the related adverse events covered by these 
algorithms will depend on the immuno-oncology agent or regimen being used. 
 

 
 
 
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92 
LIST OF ABBREVIATIONS 
Abbreviation 
Term 
ANC 
Absolute Neutrophil Count 
APC 
Antigen-presenting cell 
BID 
Twice a Day 
BMS 
Bristol-Myers Squibb Company 
BORR 
Best Objective Response Rate 
CTLA4 
cytotoxic T lymphocyte antigen 4 
CT scan 
Computed Axial Tomography scan 
CBC 
Complete Blood Count 
CR 
Complete Response 
DLT 
Dose Limiting Toxicity 
DMFS 
DSMB 
Distant metastasis-free survival 
Data Safety Monitoring Board 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
irAE 
Immune-related adverse events 
HIPAA 
Health Insurance Portability and Accountability Act 
IMAE 
Immune-mediated adverse events 
IRB 
Institutional Review Board 
irRC 
Immune-related response criteria 
irCR 
Immune-related complete response 
irPD 
Immune-related progressive dose 
FPFV 
First patient first visit 
LPFV 
Last patient first visit 
MRI 
Magnetic Resonance Imaging 
MTD 
OS 
Maximum Tolerated Dose 
Overall survival 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PO 
By Mouth 
PR 
Partial Response 
QD 
Once Daily 
SAE 
Serious Adverse Event 
SPD 
Sum of the products diameters 
SD 
Stable Disease 
TNM Staging 
Tumor, Node and Metastasis Staging 

 
 
 
93 
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