Clinical trial NCT02982954
Conditions: Renal Cell Carcinoma
Sponsor: Bristol-Myers Squibb
Start date: 2017-01-16; Completion date: 2021-10-06
Enrollment: 211 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To investigate the safety of Nivolumab in combination with Ipilimumab in subjects with previously untreated advanced or metastatic Renal Cell Cancer.

Detailed description:

Arms: arm 1: Clear-Cell Renal Cell Carcinoma (ccRCC) with Karnofsky Performance Status (KPS) ≥ 70% arm 2: Non Clear-Cell Renal Cell Carcinoma (nccRCC) with KPS ≥ 70% arm 3: Renal Cell Carcinoma (RCC) with non-active Brain Metastases, with KPS ≥70% arm 4: Renal Cell Carcinoma (RCC), regardless of any histology or existing non-active brain metastasis, with KPS 50%-60%
Interventions: intervention 1: Nivolumab intervention 2: Ipilimumab
Intervention descriptions: intervention 1: Specified dose on specified day intervention 2: Specified Dose on Specified Day

Protocol documents:
Prot_000.pdf: 


Clinical Protocol
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to  partners  to  which  BMS  has  transferred  obligations,  e.g.,  a  Contract  Research 
Organization (CRO).
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• Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection.
• Known medical condition (eg, a condition associated with diarrhea or acute diverticulitis) that, 
in  
the  
investigator’s  opinion,  would  
increase  
the  
risk  associated  with  study  participation  or 
study drug administration or interfere with the interpretation of safety results.
• Major surgery (eg, nephrectomy) less than 28 days prior to the first dose of study drug.
• Anti-cancer therapy less than 28 days prior to the first dose of study drug or palliative, focal 
radiation therapy less than 14 days prior to the first dose of study drug.
• Presence of any toxicities attributed to prior anti-cancer therapy, other than alopecia, that have 
not resolved to Grade 1 (NCI CTCAE v4) or baseline before administration of study drug.
• Any of the following laboratory test findings:
i)  WBC < 2,000/mm
3
ii) Neutrophils < 1,500/mm
3
iii) Platelets < 100,000/mm
3
iv) AST or ALT > 3 x ULN (> 5 x ULN if liver metastases are present)
v) Total Bilirubin > 1.5 x ULN (except participants with Gilbert Syndrome, who can have 
total bilirubin < 3.0 mg/dL)
vi) Serum creatinine > 1.5 x upper limit of normal (ULN) or creatinine clearance < 40 mL/min 
(measured or calculated by Cockroft-Gault formula)
Objectives and Endpoints:
Table 1.-1:  
Objectives and Endpoints
Objectives
Endpoints
Primary
• To assess the incidence of high grade (CTCAE v4 Grade 3-4 and Grade 
5)  IMAEs  in  participants  with  advanced  or  metastatic  RCC  who  are 
treated with combination therapy of nivolumab 6 mg/kg + ipilimumab 1 
mg/kg every 8 weeks alternating with nivolumab 480 mg flat dose every 
8 weeks, staggered every 4 weeks (Cohort 1)
• Incidence  of  high  grade 
(CTCAE  v4    Grade  3-4  and 
Grade 5) IMAEs 
• To assess the incidence of high grade (CTCAE v4  Grade 3-4 and Grade 
5)  IMAEs  in  participants  with  advanced  or  metastatic  RCC  who  are 
treated with combination nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) 
every 3 weeks for four doses, followed by maintenance nivolumab (480 
mg  every  4  weeks),  in  the  select  subgroups  of  mRCC  participants 
(nccRCC, asymptomatic brains metastasis, or any histology with KPS 50-
60% (Cohorts 2, 3, 4)
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the last enrolled participant completes 5 years of survival follow up from LPFT. Participants will 
be  permitted  to  continue  treatment  beyond  progressive  disease  (PD)  (RECIST  1.1)  under 
protocol-defined circumstances (See Section 7.9). No dose increases or reductions will be allowed 
for nivolumab or ipilimumab. 
The study design schematic is presented in Figure 1.
Figure 1: 
Study Design Schematic
Number of Participants: 
The  sample  size  of  the  study  is  mainly  determined  by  feasibility. The study plans to enroll 
approximately 250 participants, 200 will plan to get treatment,  Approximate participant numbers 
are: 100 in Cohort 1, 50 in Cohort 2, 25 in Cohort 3, and 25 in Cohort 4 (100 in Cohort 1 and 100 
in Cohorts 2-4 combined). The number of participants in Cohort 1 with a favorable risk score per 
IMDC prognostic criteria (no adverse prognostic factor present) will be capped at 25%. 
Treatment Arms and Duration:
• Cohort 1:Participants in Cohort 1 will receive nivolumab 6 mg/kg plus ipilimumab 1 mg/kg 
every 8 weeks. Beginning on Day 1 Week 5, participants will receive nivolumab (480 mg) as 
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a  
flat  dose  every  8  weeks.  Treatment  will  continue  until  disease  progression,  unacceptable 
toxicity, withdrawal of consent, or end of trial (2 years), whichever comes first.
• Cohorts 2, 3, and 4: Participants in Cohorts 2, 3, and 4 will receive nivolumab 3 mg/kg and 
ipilimumab 1 mg/kg every 3 weeks, for up to 4 doses. Beginning Cycle 3, 6 weeks following 
last  dose  of  combination  therapy  participants  will  then  begin  treatment  with  nivolumab 
(480 mg)  every  4  weeks  (±  3  days)  as  maintenance  therapy  until disease  progression, 
unacceptable toxicity, withdrawal of consent, or end of trial (2 years). whichever comes first.
Study treatment: 
Study Drug for CA209920
Medication
Potency
IP/Non-IP
BMS-936558-01 (Nivolumab) 
Solution for Injection
100 mg (10 mg/mL)
IP
Ipilimumab Solution for Injection  
200 mg (5 mg/mL)
IP
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2  
SCHEDULE OF ACTIVITIES
Table 2-1:  
Screening Assessments (All Participants)
Procedure
Screening
Visita
Notes
Eligibility Assessments
Informed Consent
X  
Obtain consent prior to performing any testing for eligibility
IWRS
X  
An IWRS will be used to assign participant numbers 
Inclusion/Exclusion Criteria
X
Medical History
X
Tumor Tissue Samples
X
Sufficient tumor tissue, archival or recent acquisition, (block or minimum of 10 slides; obtained 
from core biopsy, punch biopsy, excisional biopsy or surgical specimen) available to be received 
at Central Laboratory.
Safety Assessments
Physical Examination
X
Vital Signs 
X
Including BP, HR, and temperature. Obtain at the screening visit and within 72 hours prior to 
first dose
Physical Measurements (including 
performance status)
X  
Height and weight and Karnofsky Performance Status.
ECG
X  
Within 28 days prior to first dose
Serious Adverse Event Assessment 
X  
SAE assessment from the time of consent. 
Assessment of Signs and Symptoms
X  
Within 14 days prior to first dose
Concomitant Medication Collection
X  
Within 14 days prior to first dose
Laboratory Tests
X
CBC with differential, Chemistry panel including LDH, AST, ALT, ALB, ALP, T Bili, BUN or 
serum urea level, creatinine, Mg, Ca, Na, K, Cl, Glucose, amylase, lipase, TSH, Free T4, Free 
T3, hepatitis B surface antigen (HBVsAg), and hepatitis C antibody (HCV Ab) or hepatitis C 
RNA (HCV RNA), within 14 days of first dose.
Pregnancy Test (WOCBP Only) 
X  
Within 24 hours prior to first dose (serum or urine at the site).
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Table 2-1:  
Screening Assessments (All Participants)
Procedure
Screening
Visita
Notes
Efficacy Assessment 
Screening/Baseline Tumor Assessments  
X
CT/MRI of the chest, abdomen, pelvis and all known sites of disease and MRI (preferred) or CT 
contrast-enhanced scan of the Brain within 28 days prior to first dose. 
CT with oral and intravenous contrast or contrast-enhanced MRI are the preferred imaging 
modalities.
If CT iodinated contrast is contraindicated, a non-contrast CT of the chest, and contrast enhanced 
MRI abdomen, pelvis and all other known or suspected sites of disease should be imaged. (See 
Section 7.7.2.3).
a Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
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4 
OBJECTIVES AND ENDPOINTS
Table 4-1:  
Objectives and Endpoints
Objectives
Endpoints
Primary
• To  assess  the  incidence  of  high  grade  (CTCAE  v4  Grade  3-4  and 
Grade 5) IMAEs in participants with advanced or metastatic RCC  who 
are treated with combination therapy of nivolumab 6 mg/kg + ipilimumab 
1 mg/kg  every  8  weeks  alternating  with  nivolumab  480  mg  flat  dose 
every 8 weeks, staggered every 4 weeks (Cohort 1)
• incidence  of  high  grade 
(CTCAE  v4  Grade  3-4  and 
Grade 5) IMAEs 
• To  assess  the  incidence  of  high  grade  (CTCAE  v4  Grade  3-4  and 
Grade 5) IMAEs in participants with advanced or metastatic RCC  who 
are  treated  with  combination  nivolumab  (3  mg/kg)  and  ipilimumab 
(1 mg/kg)  every    3  weeks  for  four  doses,  followed  by  maintenance 
nivolumab  
(480 mg  every  4  weeks),  
in  
the  select  subgroups  of  mRCC 
participants (nccRCC, asymptomatic brains metastasis, or any histology 
with KPS 50-60% (Cohorts 2, 3, 4)
Secondary
• To characterize the outcome of all high grade (CTCAE v4  Grade 3-4 and 
Grade 5) IMAEs in participants with advanced or metastatic RCC  who 
are treated with combination therapy in different cohorts.
• Characterization  of  outcome 
of all high grade (CTCAE v4
Grade  3-4  and  Grade  5) 
IMAEs  (eg,  time  to  onset, 
time to resolution, percentage 
of  patients  who  received 
immune   
modulating 
medication)
• To  assess  efficacy  of  nivolumab in  combination  with  ipilimumab by 
measuring, progression-free survival (PFS 1 at time of initial progression; 
objective response rate (ORR), time to response (TTR), and duration of 
response  (DOR),  in  all  treated  participants  in  different  cohorts  using 
RECIST 1.1. 
• PFS 1, ORR, TTR, DOR
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• The study design schematic is presented in Figure 5.1-1.
Figure 5.1-1:  
Study Design Schematic
5.1.1  
Data Monitoring Committee and Other External Committees
A Scientific Steering Committee (SSC) comprised of clinical experts in RCC will closely review 
the safety data throughout the study, especially for the special mRCC patient groups (Cohort 2, 3, 
and  4).  The  safety  review  plan  will  include, but  not  be limited  to  the  following  frequency. 
Additional reviews may be triggered on an ad hoc basis by the BMS CA209920 study team. 
Safety  review  for  all  treated  patients  will  take  place,  when  any  of  the  following  criteria  are 
satisfied:
• When a minimum of 5 patients with KPS of 50-60% in Cohort 4 have received at least two 
doses of combination therapy on study to assess safety and evaluate further enrollment  
into 
cohort 4, 
OR
• When a minimum of 10 patients in Cohort 2-4 have received at least two doses of combination 
therapy on study to assess safety and efficacy and evaluate further enrollment into the cohorts.
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6 
STUDY POPULATION
Males  and  females,  age  18  years or  older,  with  histologically  confirmed,  previously  untreated, 
advanced or metastatic RCC will be eligible for the study. 
For entry into the study, the following criteria MUST be met.
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6.1  
Inclusion Criteria
Inclusion
1) Signed Written Informed Consent
a) Participants must have signed and dated an IRB/IEC-approved written informed consent 
form in accordance with regulatory and local guidelines. This must be obtained before the 
performance of any protocol-related procedures that are not part of normal participant care.
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory testing, and other requirements of the study
2) Type of Participant and Target Disease Characteristics
a) Advanced  
(not amenable  
to  curative  surgery  or  
radiation  
therapy)  or  metastatic  
(AJCC 
Stage IV) RCC 
b) Histologically  confirmed,  previously  untreated  (treatment-naive)  RCC (as  defined  in 
Appendix 3):
i) Predominant clear-cell.
ii) Non-clear cell histology including:
(1).papillary
(2).chromophobe 
(3).translocation associated.
(4).collecting duct
(5).medullary
(6).any pathology unclassified.
c) No prior systemic therapy for RCC with some exceptions: 
i)  One  prior  adjuvant  or  neoadjuvant  therapy  for  completely  resectable  RCC  if  such 
therapy  did  not  include  checkpoint  inhibitors  and  if  recurrence  occurred  at  least 
6 months after the last dose of adjuvant or neoadjuvant therapy.
d) Participants  with  brain  metastases  will  be  allowed  
if  
they  are  asymptomatic  and  not on 
systemic  corticosteroids  or  receiving  radiation  treatment  for  at  least  14  days  prior  to 
beginning protocol therapy. Brain lesion(s) that are < 10 mm or that have been previously 
irradiated will only be assessed as non-target lesion per RECIST 1.1. Brain lesions that are 
≥10 mm and that have not been previously irradiated will be assessed as target lesions per 
RECIST 1.1.
i) Participants  who  are  found  on  screening  CT/MRI  
to  have  brain metastases  will  be 
enrolled to Cohort 3 or 4 (depending on the KPS level)  
if they do not require active 
treatment (radiation treatment/corticosteroids) 
ii) Participants who are found on screening CT/MRI to have brain metastases that require 
immediate treatment (radiation treatment/corticosteroids) will be re-enrolled to Cohort 
3 or 4 (depending on the KPS level) after completing active treatment
e) Measurable disease as per RECIST 1.1. Participant must have extracranial  metastasis as 
measurable disease (Appendix 4)
f)  Karnofsky Performance Status (KPS) of at least 70% for Cohort 1, 2, and 3; KPS of 50-60% 
for Cohort 4 (Appendix 5)
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g) Participants with favorable, intermediate and poor risk categories will be eligible for the 
study  in  all  cohorts  per International  Metastatic RCC  Database Consortium  (IMDC) 
prognostic criteria (Appendix 6). Enrollment of participants with a favorable risk score (no 
adverse prognostic factors present) will be capped to 25% of entire Cohort 1 population.  
h) Tumor tissue (FFPE archival or recent acquisition) need be available to be received by the 
central vendor (block or unstained slides). (Note: Fine Needle Aspiration [FNA] and bone 
metastases samples are not acceptable for submission).
3) Age and Reproductive Status 
a) Males and Females, ≥18 years of age
b) Women  of  childbearing  potential  (WOCBP)  must  have  a  negative serum  or  urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study treatment.
c) Women must not be breastfeeding.
d) Women  of  childbearing  potential  (WOCBP)  must  agree  to  follow instructions  for 
method(s) of contraception for the duration of study treatment and 5 months after the last 
dose of study treatment {i.e., 30 days (duration of ovulatory cycle) plus the time required 
for the investigational drug to undergo approximately five half-lives. 
e) Males  who  are  sexually  active  with  WOCBP  must  agree  to  follow  instructions  for 
method(s) of contraception for the duration of study treatment and 7 months after the last 
dose of study treatment {i.e., 90 days (duration of sperm turnover) plus the time required 
for the investigational drug to undergo approximately five half-lives.} -
f)  Azoospermic  males  are  exempt  from  contraceptive  requirements.  WOCBP  who  are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, 
on  
the  importance  of  pregnancy  prevention  and  
the  implications of  an  unexpected  pregnancy. 
Investigators shall advise on the use of highly effective methods of contraception, (Appendix 7)
which have a failure rate of < 1% when used consistently and correctly
6.2  
Exclusion Criteria
1) Medical Conditions
a) Women  with  a  positive  pregnancy  
test  at  enrollment or  prior to  administration  of  study 
medication
b) Any active or recent history of a known or suspected autoimmune disease or recent history 
of a syndrome that required systemic corticosteroids (> 10 mg daily prednisone equivalent) 
or immunosuppressive medications except for syndromes which would not be expected to 
recur  
in  
the  absence  of  an  external  
trigger.  Participants  with vitiligo  or  
type I  diabetes 
mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone 
replacement are permitted to enroll.
c) Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone 
equivalents) or other immunosuppressive medications within 14 days prior to first dose of 
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study  drug. Inhaled  steroids  and  adrenal  replacement  steroid  doses  > 10 mg  daily 
prednisone equivalents are permitted in the absence of active autoimmune disease.
d) Uncontrolled adrenal insufficiency.
e) Prior malignancy active within the previous 3 years except for locally curable cancers that 
have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder 
cancer, or carcinoma in situ of the prostate, cervix, or breast.
f)  Known  history  of  
testing  positive  for  human  immunodeficiency virus  (HIV)  or  known 
acquired immunodeficiency syndrome (AIDS) as per local requirements.
g) Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection.
h) Known medical condition (eg, a condition associated with diarrhea or acute diverticulitis) 
that,  in  the  investigator’s  opinion,  would  increase  the  risk  associated  with  study 
participation  or  study  drug  administration  or  interfere  with  the  interpretation  of  safety 
results.
i)  Major surgery (eg, nephrectomy) less than 28 days prior to the first dose of study drug.
2) Prior/Concomitant Therapy
a) Prior systemic treatment in the metastatic setting with VEGF or VEGF receptor targeted 
therapy  (including,  but  not  limited  to,  sunitinib,  pazopanib,  axitinib,  tivozanib,
bevacizumab, cabozantinib, and lenvantinib)
b) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody,  or  any  other  antibody  or  drug  specifically  targeting T-cell  co-stimulation  or 
checkpoint pathways. This includes the utilization of these agents in the neo-adjuvant or 
adjuvant setting.  
c) Anti-cancer therapy  
less  
than  28  days  prior to the  
first  dose of  study  drug or  palliative, 
focal radiation therapy less than 14 days prior to the first dose of study drug.
3) Physical and Laboratory Test Findings
a) Presence of any toxicities attributed to prior anti-cancer therapy, other than alopecia, that 
have not resolved to Grade 1 (NCI CTCAE v4) or baseline before administration of study 
drug.
b) Any of the following laboratory test findings:
i)  WBC < 2000/μL
ii) Neutrophils < 1500/μL
iii) Platelets < 100*103/μL
iv) Hemoglobin < 9.0 g/dL
v) Serum creatinine  >1.5 x ULN or calculated creatinine clearance < 40 mL/min (using 
the Cockcroft-Gault formula)
vi) AST/ALT: > 3.0 x ULN
vii) Total bilirubin > 1.5 x ULN (except participants with Gilbert Syndrome who must have 
a total bilirubin level of < 3.0x ULN)
viii)  Any positive test result for hepatitis B virus or hepatitis C virus indicating presence 
of  virus,  e.g.  Hepatitis  B  surface  antigen  (HBsAg,  Australia  antigen)  positive,  or 
Hepatitis C antibody (anti-HCV) positive (except if HCV-RNA negative).
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4) Allergies and Adverse Drug Reaction
a) History of severe hypersensitivity reactions to other monoclonal antibodies
b) History  of  allergy  or  intolerance  (unacceptable  AEs)  to  study  drug  components  or 
Polysorbate-80-containing infusions
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to continue 
as a participant. Strict conditions apply and Bristol-Myers Squibb approval is required.
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(e.g., infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can  be used. It is  
imperative that participants  
fully 
meet all eligibility criteria.
6.3  
Lifestyle Restrictions
Not applicable. No restrictions are required
6.4  
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from regulatory 
authorities.  Minimal  information  includes  date  of  consent,  demography,  screen  failure  details, 
eligibility criteria, and any serious AEs.
6.4.1  
Retesting During Screening or Lead-In Period
Participant  Re-enrollment:  This  study  permits  the  re-enrollment  of  a  participant  that  has 
discontinued  the  study  as  a  pre-treatment  failure  (ie,  participant  has  not  been  treated).  If  re-
enrolled,  
the  participant  must  be  
re-consented.  Retesting  of  
laboratory  parameters  and/or  other 
assessments  within  any  single Screening  will be  permitted  
(in  addition  
to  any  parameters  
that 
require a confirmatory value).
The most current result prior to Treatment assignment is the value by which study inclusion will 
be  assessed,  as  
it  
represents the  participant’s  most  current  clinical  state.  Laboratory  parameters 
and/or assessments that are included inTable 2-1, Screening Procedural Outline may be repeated 
in an effort to find all possible well-qualified participants. 
Consultation with the Medical Monitor may be needed to identify whether repeat testing of any 
particular parameter is clinically relevant. 
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7  
TREATMENT
Study  
treatment  
is  defined  as  any  
investigational  
treatment(s),  marketed  product(s),  placebo  or 
medical  device  intended  to  be  administered  to  a  study  participant  according  to  the  study 
randomization or treatment allocation.
Study  treatment  includes  both  Investigational  [Medicinal]  Product  (IP/IMP)  and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in  a  clinical  study,  including  products  already  with  a  marketing  authorization  but  used  or 
assembled  (formulated  or  packaged)  differently  than  the  authorized  form,  or  used  for  an 
unauthorized indication, or when used to gain further information about the authorized form.
In this protocol, nivolumab and ipilimumab are investigational products. 
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products.
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Table 7-1:  
Study treatments for CA209920
Product Description / 
Class and Dosage 
Form
Potency  
IP/Non-IMP
Blinded or 
Open Label
Packaging / 
Appearance
Storage Conditions
(per label)
BMS-936558-01 
(Nivolumab) Solution 
for Injection
100 mg (10 mg/mL)  
IP  
Open Label
10 mL per vial 
(10 vials/carton)
Store at 2° - 8 °C.
Protect from light and 
freezing.
Ipilimumab Solution 
for Injection
200 mg (5 mg/mL)  
IP  
Open Label
40 mL per vial 
(4 vials/carton)
Store at 2° - 8 °C.
Protect from light and 
freezing.
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7.1  
Treatments Administered
The selection and timing of dose for each participant is as follows:
Table 7.1-1:  
Selection and Timing of Dose
Study Treatment
Unit dose 
strength(s)/Dosage 
level(s)
Dosage formulation
Frequency of 
Administration
Route of Administration
Cohort 1
Nivolumab 6 mg/kg
Ipilimumab 1 mg/kg
Nivolumab 480 mg
Combination: D1W1 and then 
every 8 weeks,
Monotherapy beginning 
D1W5 of C1, and then every 8 
weeks
Nivolumab IV 
Ipilimumab IV
Cohort 2, 3, and 4
Nivolumab 3 mg/kg
Ipilimumab 1 mg/kg
Nivolumab 480 mg
Combination therapy: every 3 
weeks for 4 doses
Maintenance monotherapy 
every 4 weeks afterwards.
Nivolumab IV 
Ipilimumab IV
Participants should begin study treatment within 5 calendar days of treatment assignment. 
Where  dosing  calculations  should  be  based  on  
the  body  weight  assessed  at  baseline.  It  
is  not 
necessary to re-calculate subsequent doses if the participant weight is within 10% of the weight 
used to calculate the previous dose. All doses should be rounded up or to the nearest milligram per 
institutional standard.
When study drugs (nivolumab and ipilimumab) are to be administered on the same day, nivolumab 
is  
to  be  administered  
first.  Nivolumab  
infusion  must  be promptly  
followed  by  a  saline  
flush  
to 
clear  
the  line  of  nivolumab  before  starting  
the  ipilimumab  infusion.  The  second  infusion  will 
always be the ipilimumab study drug and will start after the infusion line has been flushed, filters 
changed and patient has been observed to ensure no infusion reaction has occurred.  The time in 
between infusions is expected to be approximately 30 minutes but may be more or less depending 
on the situation. 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) is to be administered as an IV infusion through 
a 0.2-micron to 1.2-micron pore size, low-protein binding  
in-line  
filter at the protocol-specified 
doses. It is not to be administered as an IV push or bolus injection. Nivolumab injection can be 
infused  undiluted  (10  mg/mL)  or  diluted  with  0.9%  Sodium  Chloride  Injection,  USP  or  5% 
Dextrose Injection, USP to protein concentrations as low as 1 mg/mL. Instructions for dilution and 
infusion  of  nivolumab  
injection  may  be provided  
in  
the  clinical  protocol,  pharmacy  binder,  or 
pharmacy reference sheet. Care must be taken to assure sterility of the prepared solution as the 
product does not contain any antimicrobial preservative or bacteriostatic agent
There will be no dose escalations or reductions of nivolumab or ipilimumab allowed. For dosing 
cycles every 8 weeks, participants may be dosed within a ±3 day window. Premedications are not 
recommended for the first dose of nivolumab.
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Doses  of  nivolumab or  
ipilimumab may  be  
interrupted,  delayed,  or discontinued  depending  on 
how well the participant tolerates the treatment. Dosing visits are not skipped, only delayed.
Participants should be carefully monitored for infusion reactions during nivolumab administration. 
If an acute infusion reaction is noted, participants should be managed according to Section 7.4.2.
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin containers and 
infusion sets, and glass bottles.
Ipilimumab  
injection  can  be  used  for  
IV  administration  without dilution  after  
transferring  
to  a 
PVC,  non-PVC/non-DEHP  or  glass  container  and  is  stable  for  24  hours  at  2-8°C  or  room 
temperature/room  light  (RT/RL).  For  ipilimumab  storage  instructions,  refer  to  ipilimumab  IB 
and/or pharmacy reference sheets.
Separate infusion bags and filters should be used when administering nivolumab and ipilimumab 
on the same day.
Ipilimumab is to be administered as a 30 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  injections.  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.  
7.1.1  
Cohort 1
Participants should receive nivolumab at a dose of 6 mg/kg as about a 60-minute IV infusion, and 
ipilimumab at a dose of 1 mg/kg as about an 30-minute IV infusion on Day 1 Week 1 of each cycle 
(every 8 weeks), until progression, unacceptable toxicity, withdrawal of consent, the study ends or 
up to a maximum of 24 month whichever occurs first. Participants should begin study treatment 
within  5  calendar  days  of  treatment  assignment. Beginning  on  Day  1  of  Week  5  of  Cycle  1, 
participants will receive nivolumab 480 mg flat dose, as a 60 minute infusion, and then again every 
8 weeks until progression, unacceptable toxicity, withdrawal of consent, the study ends or up to a 
maximum of 24 month whichever occurs first.
7.1.2  
Cohorts 2, 3, and 4
Participants in Cohorts 2, 3, and 4, will receive nivolumab at a dose of 3 mg/kg as a 60 minute 
infusion, and ipilimumab at a dose of 1 mg/kg as a 30 minute infusion on Day 1 Week 1 and Day 1 
Week 4 of each cycle (every 6 weeks) until for up to 4 doses (2 cycles). Participants should begin 
study treatment within 5 calendar days of treatment assignment. Beginning with Cycle 3 (6 weeks
[±3 days] from last combo dose), participants in Cohorts 2, 3 and 4 will receive nivolumab at a 
dose of 480 mg as a 60 minute infusion every 4 weeks (±3 days) until progression, unacceptable 
toxicity,  withdrawal  of  consent, the  study  ends,  or  up to  a  maximum  of  24  months,  whichever 
occurs first. 
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7.2  
Method of Treatment Assignment
After  the  participant’s  eligibility  is  established  and  informed  consent  has  been  obtained,  the 
participant will be enrolled and a number will be assigned through an interactive voice response 
system  (IVRS).  Also,  
the  IVRS  will  be  used  to manage  enrollment of  participant  subgroups. 
Specific instructions and procedures for using IVRS will be provided to the investigational site in 
a separate document/ manual.
The  investigator  (or  designee)  will  register  the  participant  for  enrollment  by  following  the 
enrollment procedures established by BMS. The following information is required for enrollment:
• Date of informed consent
• Date of birth
• Gender at birth
• Confirmed RCC histology
• Confirmed presence or absence of brain metastases
• Performance Status
7.3  
Blinding
This is an open-label study, blinding procedures are not applicable.
7.4  
Dosage Modification
Dose reductions or dose escalations of nivolumab or ipilimumab are not permitted.
7.4.1  
Study Treatment Dose Delay Criteria
Study treatment administration should be delayed for the following:
• Grade 2 non-skin, drug-related adverse event, with the exception of fatigue
• Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities
• Grade 3 skin, drug-related adverse event
• Grade 3 drug-related laboratory abnormality, with the following exceptions: 
− Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
− Grade ≥3 AST, ALT, Total Bilirubin will require dose discontinuation (see Section8.1.1)
• Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
Participants  who  require  delay  of  study  treatment  should  be  re-evaluated  weekly  or  more 
frequently if clinically indicated and resume nivolumab dosing when re-treatment criteria are met.
During Cycles 1 and 2, both nivolumab and ipilimumab must be delayed at the same time.
Because of the potential for clinically meaningful nivolumab or ipilimumab-related AEs requiring 
early  recognition  and  prompt  intervention,  management  algorithms  have  been  developed  for 
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suspected  pulmonary  toxicity,  GI,  hepatotoxicity,  endocrinopathy,  skin  toxicity,  neurological 
toxicity and renal toxicity. 
In  order  
to  standardize  
the  management of overlapping  adverse  event  management  algorithms 
present  
in both the BMS-936558 (nivolumab) and ipilimumab IB (GI, hepatic, and endocrine
algorithms), the recommendations are to follow the BMS-936558 (nivolumab) IB adverse event 
algorithms as opposed to the ipilimumab IB algorithms.
The algorithms recommended for utilization in are included in Appendix 8.
7.4.2  
Treatment of Nivolumab or Ipilimumab Related Infusion Reactions
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, each is 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction  were  to  occur,  it  might  manifest  with  fever,  chills,  rigors,  headache,  rash,  pruritus, 
arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 
or 4 infusion reactions should be reported within 24 hours to the BMS Study Medical Monitor and 
reported as an SAE if it meets the criteria. Infusion reactions should be graded according to NCI 
CTCAE (Version 4) guidelines.
Treatment recommendations are provided below and  may  be  modified based on local treatment 
standards and guidelines, as appropriate:
For  Grade  1  symptoms:  (mild  reaction;  infusion  interruption  not  indicated;  intervention  not 
indicated):
• Remain  at  bedside  and  monitor  participant until  recovery  from  symptoms.  The  following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab administrations.
For Grade 2 symptoms: (moderate reaction required therapy or infusion interruption but responds 
promptly  
to  symptomatic  
treatment  
(eg,  antihistamines,  non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids); prophylactic medications indicated for ≤ 24 
hours):
• Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, and treat 
the   participant   with   diphenhydramine   50   mg   IV   (or   equivalent)   and/or 
acetaminophen/paracetamol 325 to 1000 mg; remain at bedside and monitor participant until 
resolution  of  symptoms.  Corticosteroid  and/or  bronchodilator  therapy  may  also  be 
administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% of 
the original infusion rate when symptoms resolve; if no further complications ensue after 30 
minutes, the rate may be increased to 100% of the original infusion rate. Monitor participant 
closely. If symptoms recur, then no further nivolumab or ipilimumab will be administered at 
that visit.
• For  future  infusions,  the  following  prophylactic  premedications  are  recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
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should  be  administered  at  least  30  minutes  before  nivolumab  infusions.  If  necessary, 
corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used.
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial  
improvement;  hospitalization  
indicated  
for other  clinical  sequelae  
(eg,  
renal  
impairment, 
pulmonary infiltrates). Grade 4: Life-threatening; pressor or ventilatory support indicated):
• Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV infusion of normal 
saline and treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 
mg  of  a  1:1000  solution  for  subcutaneous  administration  or  0.1 to  0.25  mg  of  a  1:10,000 
solution  injected  slowly  for  IV  administration,  and/or  diphenhydramine  50  mg  IV  with 
methylprednisolone  100  mg  
IV  
(or  equivalent),  as  needed.  Participant  should  be  monitored 
until  
the  Investigator  
is  comfortable  
that  
the  symptoms  will  not  recur.  Study  drug  will  be 
permanently  discontinued.  Investigators  should  follow  
their  institutional  guidelines  for  
the 
treatment  of  anaphylaxis.  Remain at  bedside  and  monitor  participant  until  recovery  of  
the 
symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus  within  1  week  after  treatment),  symptomatic  treatment may  be  given  (eg,  oral 
antihistamine or corticosteroids).
7.4.3  
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology (I-O) agents are associated with  AEs that can differ  
in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab and ipilimumab are considered immuno-
oncology  agents  in  this  protocol.  Early  recognition  and  management  of  AEs  associated  with 
immuno-oncology  agents  may  mitigate  severe  toxicity.  Management  Algorithms  have  been 
developed to assist investigators in assessing and managing the following groups of AEs:
• Gastrointestinal
• Renal
• Pulmonary
• Hepatic
• Endocrinopathy
• Skin
• Neurological
The above algorithms are found in both the nivolumab and ipilimumab Investigator Brochures,
as well as in Appendix 8.
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7.8 
Treatment After the End of the Study
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible  to  receive  BMS  supplied  study  treatmentfor  the  maximum treatment  duration 
specified in Sections 7.1.1 and 7.1.2.
Study treatment will be provided via an extension of the study, a rollover study requiring approval 
by  responsible  health  authority  and  ethics  committee  or  through  another  mechanism  at  the 
discretion of BMS.
7.9  
Treatment Beyond Progression 
Accumulating  evidence  indicates  a  minority  of  participants  treated  with  immunotherapy  may 
derive  clinical  benefit  despite  
initial  evidence  of  PD.  Participants  will  be  permitted to  continue 
study treatment beyond initial RECIST 1.1 defined PD as long as the following criteria are met:
1) Investigator-assessed clinical benefit
2) Tolerance of study drug
3) Stable performance status
4) Treatment  beyond progression  will  not  delay  an  imminent  intervention  to  prevent  serious 
complications of disease progression (eg, CNS metastases)
5) Participant  provides  written  
informed  consent  prior to  
receiving  additional  study  
treatment, 
using an ICF describing any reasonably foreseeable risks or discomforts, or other alternative 
treatment options.
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The decision to continue treatment beyond initial progression should be discussed with the BMS 
medical Monitor and documented in the study records.
A radiographic assessment/ scan should be performed within 8 weeks of original PD to determine 
whether there has been a decrease in the tumor size, or continued PD. The assessment of clinical 
benefit  should  be  balanced  by  clinical  judgment  as  to  whether  the  participant  is  clinically 
deteriorating and unlikely to receive any benefit from continued study treatment.
If  
the  
investigator  
feels  
that  
the  participant  continues  
to  achieve  clinical  benefit  by  continuing 
treatment, the participant should remain on the trial and continue to receive monitoring according 
to the Time and Events Schedule (Section 2).
For the participants who continue study therapy beyond progression, further progression is defined 
as an additional 20% increase in tumor burden volume from time of initial PD. This includes an 
increase  in  the  sum  of  all  target  lesions  and/  or  
the  development  of  new  measurable  lesions. 
Treatment should be discontinued permanently upon documentation of further disease progression
New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm).  Any  new  lesion  considered  non-measureable  at  the  time  of  initial progression  may 
become measureable and therefore included in the tumor burden volume if the longest diameter 
increases to at least 10 mm (except for pathological lymph nodes which must have a short axis of 
at least 15 mm).
Participants  with  global  deterioration  of  health  status  (as  determined  by  
the  investigator)  who 
require discontinuation of treatment without objective evidence of disease progression at the time 
of  treatment  discontinuation  should  be  reported  as  ‘symptomatic  deterioration’.  Every  effort 
should  be  made  to  document  objective  progression  (ie,  radiographic  confirmation)  even  after 
discontinuation of treatment.
8  
DISCONTINUATION CRITERIA
8.1  
Discontinuation from Study Treatment
Participants  MUST  discontinue  investigational  product  (and  non-investigational  product  at  
the 
discretion of the investigator) for any of the following reasons:
• Participant’s  request  
to  stop  study  
treatment.  Participants  who  
request  
to  discontinue  study 
treatment  will  
remain  
in  
the  study  and  must  continue  
to  be  
followed  
for  protocol  specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information
• Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the participant
• Termination of the study by Bristol-Myers Squibb (BMS)
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• Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness
• Additional protocol specified criteria for discontinuation (see Section 8.1.1)
Refer to the Schedule of Activities for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that can be completed
In the case of pregnancy, the investigator must immediately notify the Sponsor or designee of this 
event. In most cases, the study drug will be permanently discontinued in an appropriate manner 
(eg,  dose  
tapering  if  necessary  for  participant  safety).  Please  contact  
the  Sponsor  or  designee 
within 24 hours of awareness of the pregnancy. If the investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of study drug, a discussion between the investigator 
and the Sponsor or designee must occur.
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2. The only exception to this requirement is when a participant 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (i.e., is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page.
The assessment for discontinuation of nivolumab should be made separately from the assessment 
made  for  discontinuation  of  ipilimumab.  Although  
there  
is  overlap  among the  discontinuation 
criteria, if discontinuation criteria are met for ipilimumab but not for nivolumab, treatment with 
nivolumab may continue if ipilimumab is discontinued.
If  a  participant  in  any  of  the  nivolumab/ipilimumab  combination  cohortsmeets  criteria  for 
discontinuation and investigator is unable to determine whether the event is related to both or one 
study drug, the participant should discontinue both nivolumab and ipilimumab and be taken off 
the treatment phase of the study.
8.1.1  
Dose Discontinuation
Study treatment should be permanently discontinued for the following:
• Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment
• Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, or recurs with the following 
exceptions  for  laboratory  abnormalities,  diarrhea,  colitis,  neurologic  toxicity,  drug-related 
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uveitis,  pneumonitis,  bronchospasm,  hypersensitivity  reactions,  infusion  reactions,  and 
endocrinopathies:
− Grade  3  drug-related  diarrhea,  colitis,  neurologic  toxicity,  uveitis,  pneumonitis, 
bronchospasm,  hypersensitivity  reaction,  or  infusion  reaction  of  any  duration  requires 
discontinuation
− Grade  3 drug-related  endocrinopathies, adequately  controlled  with  only  physiologic 
hormone  replacement  do  not  require  discontinuation.  Adrenal  insufficiency  requires 
discontinuation regardless of control with hormone replacement. 
− 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:
o Grade ≥3 drug-related AST, ALT or Total Bilirubin requires discontinuation*
o Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN
* In most cases of Grade 3 AST or ALT elevation, study drug(s) will be permanently discontinued. 
If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study drug(s), a discussion between the investigator and the BMS Medical Monitor/designee must 
occur.
• Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited 
to  creatinine,  AST,  ALT, or  Total  Bilirubin),  except  
for the  
following  events  which  do  not 
require discontinuation:
− Grade 4 neutropenia ≤7 days
− Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
− Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
− Grade 4 drug-related endocrinopathy adverse events, such as, hyper- or hypothyroidism, 
or  glucose  intolerance,  which  resolve  or  are  adequately  controlled  with  physiologic 
hormone  
replacement  
(corticosteroids,  
thyroid  hormones)  or  glucose-controlling  agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor.
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• Any event that leads to delay in dosing lasting > 8 weeks during Cycle 1- 2, and >10 weeks in 
cycle 3 or later for Cohorts 2-4, and >10 weeks for Cohort 1, from the previous dose requires 
discontinuation, with the following exceptions:
− Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events 
are allowed. 
− Dosing delays lasting longer than the number of weeks allowed for the respective cohorts
that occur for non-drug-related reasons may be allowed if approved by the BMS medical 
monitor. 
Prior to re-initiating treatment in a participant with a dosing delay lasting > 8 weeks for Cohorts 2 
through 4, or >10 weeks for Cohort 1, the BMS medical monitor must be consulted and provide 
written  approval  for  participants  with  expected  clinical  benefit  as  per  investigator  assessment. 
Tumor assessments should continue as per protocol even if dosing is delayed. Periodic study visits 
to assess safety and laboratory studies should also continue every 6 weeks or more frequently if 
clinically indicated during such dosing delays.
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued nivolumab dosing.
8.1.2  
Criteria to Resume Treatment
Missed doses of nivolumab and/or ipilimumab should be administered as soon as the participant
meets criteria to resume treatment. If a dose has been missed, the participant should not wait until 
the next scheduled dosing date.
Participants may resume treatment with study drug when the drug-related AE(s) resolve to Grade 
≤1 or baseline value, with the following exceptions:
• Participants may resume treatment in the presence of Grade 2 fatigue
• Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity
• For participants with Grade 2 AST, ALT and/or Total Bilirubin  Abnormalities, dosing  may 
resume  when  laboratory  values  return  
to  baseline  and  management  with  corticosteroids,  if 
needed, is complete.
• Participants  with  combined  Grade  2  AST/ALT AND  total  bilirubin  values  meeting 
discontinuation parameters (Section 8.1.1) should have treatment permanently discontinued. 
• Drug-related  pulmonary  
toxicity,  diarrhea  or  colitis  must have  resolved  
to  baseline  before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid  taper  over  at  least  1  month  may  be  eligible  for  retreatment  if  discussed  with  and 
approved by BMS Medical Monitor.
• Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone  replacement  may  resume  treatment  after  consultation  with  the  BMS  Medical 
Monitor. 
• Adrenal  insufficiency  requires  discontinuation  regardless  of  control  with  hormone 
replacement.
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If treatment is delayed > 8weeks for Cohorts 2 through 4, or >10 weeks for Cohort 1, the participant 
must be permanently discontinued from study therapy, except as specified in Section 8.1.1.
For  participants  
in  Cohort 1, during  Cycles  1  and  2,  both  nivolumab  and  
ipilimumab  must  be 
resumed on the same day. For participants in Cohort 2 to 4, all four doses of nivolumab combined 
with ipilimumab must be given prior to beginning nivolumab monotherapy (Cycle 3 and beyond). 
Participants in any cohort, who discontinue combination therapy early due to an adverse event, 
may  be  eligible  
to  
receive  nivolumab  monotherapy  (480  mg  every 4  weeks),  contingent  upon 
discussion with, and approval by the Medical Monitor.
If  the  participant is  unable  to  receive  either  combination  therapy  or  nivolumab  monotherapy 
permanent discontinuation is required.
8.1.3  
Post-Study Treatment Study Follow-up
BMS may request that survival data be collected on all treated participants outside of the protocol 
defined window (Schedule of Activities, Section 2). At the time of this request, each participant 
will be contacted to determine their survival status unless the participant has withdrawn consent 
for all contacts or is lost to follow-up.
8.2  
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant  specifically  withdraws  consent  for  any  further  contact  with  him/her  or  persons 
previously authorized by participant to provide this information. 
• Participants  should  notify  
the  
investigator  of  
the  decision  
to withdraw  consent  
from  future 
follow-up in writing, whenever possible.
• The  withdrawal  of  consent  should  be  explained  in  detail  in  the medical  records  by  the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or  also  from  study  procedures  and/or  post  treatment  study  follow-up,  and  entered  on  the 
appropriate CRF page.
• In  the  event  
that  vital  status  (whether  
the  participant  is  alive  or  dead)  is  being  measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
• If  
the  participant  withdraws  consent  for  disclosure  of  future  
information,  
the  sponsor  may 
retain and continue to use any data collected before such a withdrawal of consent.
8.3  
Lost to Follow-Up
• All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.
• Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented  phone  calls,  
faxes,  or  emails  as  well  as lack  of  
response  by  participant  
to  one 
registered mail letter. All attempts should be documented in the participant’s medical records.
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• If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.
• If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has  been  included  in  the  participant’s  informed  consent,  then  the  investigator may  use  a 
Sponsor  retained  third-party  representative  to  assist  site  staff  with  obtaining  participant’s 
contact  information  or  other  public  vital  status  data  necessary  to  complete  the  follow-up 
portion of the study. 
• The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.
• If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
9  
STUDY ASSESSMENTS AND PROCEDURES
• Study procedures and timing are summarized in the Schedule of Activities. 
• Protocol waivers or exemptions are not allowed.
• All  immediate  safety  concerns  must  be  discussed  with  the  Sponsor  immediately upon 
occurrence  or  awareness  to  determine  if  the  participant  should continue  or  discontinue 
treatment.
• Adherence  to  
the  study  design  requirements,  including  those  specified  in  the  Schedule  of 
Activities, is essential and required for study conduct.
• All  screening  evaluations  must  be  completed  and  reviewed  to  confirm  that  potential 
participants  meet  all eligibility  criteria  before  treatment  allocation.  The  investigator  will 
maintain a screening log to record details of all participants screened and to confirm eligibility 
or record reasons for screening failure, as applicable.
• Procedures  conducted  as  part  of  
the  participant’s  routine  clinical  management  (e.g.,  blood 
count)  and  obtained  before  signing  of  informed  consent  may  be  utilized  for  screening  or 
baseline  purposes  provided  
the  procedure  meets  
the  protocol-defined  criteria  and  has  been 
performed within the timeframe defined in the Schedule of Activities.
9.1  
Efficacy Assessments
Study  evaluations  will  
take  place  
in  accordance  with  
the  Schedule  of  Assessment  
(Section  2). 
Baseline assessments should be performed within 28 days prior to first dose utilizing CT or MRI. 
In addition to chest, abdomen, pelvis, and brain, all known sites of disease should be assessed at 
baseline. Participants who cannot receive IV contrast for CT at the start of study should be imaged 
by  MRI  of  abdomen/pelvis  with  IV  contrast  and  CT  of  chest  without  contrast.  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. Participants  
initially  
imaged with CT of 
chest, abdomen, and pelvis with IV contrast who can no longer receive contrast can be monitored 
by CT of chest, abdomen, and pelvis without IV contrast. Please refer to additional precautions 
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regarding  
IV  contrast  
in Section  7.7.2.3.  Participants  
in  all  cohorts  will  be  evaluated  
for tumor 
response at the following intervals and time points: 
• First  
tumor  assessment  should  be  performed  at  12  weeks  (±1  week)  following  first  dose. 
Subsequent tumor assessments should occur every 8 weeks (±1week) up to first 13 months, 
then every 12 weeks until disease progression or treatment discontinuation, whichever is later
For Cohorts 3 and 4: Brain lesion(s) that are < 10 mm or that have been previously irradiated will 
only  be assessed as  non-target lesion per RECIST 1.1. Brain  
lesions that are ≥10 mm and that 
have not been previously irradiated will be assessed as target lesions per RECIST 1.1.
Participants  will  be  permitted  
to  continue  
treatment  beyond  PD (RECIST  1.1)  under  protocol-
defined circumstances (See Section 7.9).Tumor assessments for ongoing study treatment decisions 
will  be  completed  by  the  investigator  using  RECIST  (Response  Evaluation  Criteria  in  Solid 
Tumors) 1.1 criteria.
9.1.1  
Imaging Assessment for the Study
Images will be submitted to the local lab, and read locally by the site Radiologist. 
Table 9.1.1-1:  
Imaging Assessment Schedule (Cohort 1) 
Study Day
Event Relative to Dosing
CT/MRI
Screening
Pre-dose
X
Week 12 (±1 week)
Post-dose
X
Every 8 weeks  (±1 week)
Post-dose
X
Every 12 weeks  (±1 week), after 
Month 13 of treatment 
Post-dose
X
Table 9.1.1-2:  
Imaging Assessment Schedule (Cohorts 2, 3 and 4)
Study Day
Event Relative to Dosing
CT/MRI
Screening
Pre-dose
X
Week 12 (±1 week)
Post-dose
X
Every 8 weeks  (±1 week)
Post-dose
X
Every 12 weeks  (±1 week), after 
Month 13 of treatment 
Post-dose
X
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9.2 
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 9.
AEs  will  be  
reported  by  
the participant  
(or,  when  appropriate, by  a  caregiver,  surrogate, or the 
participant
's legally authorized representative). 
The  investigator  and  any  designees  are  responsible  for  detecting,  documenting, and  reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
Immune-mediated  adverse  events  are  AEs  consistent  with  an  
immune-mediated  mechanism  or 
immune-mediated  component  for  which  non-inflammatory  etiologies  (eg,  infection  or  tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which were 
exacerbated  by  
the  induction  of  autoimmunity.  Information  supporting  
the  assessment  will  be 
collected on the participant’s case report form.
Contacts for SAE reporting specified in Appendix 9. 
9.2.1  
Time Period and Frequency for Collecting AE and SAE Information
The collection of non-serious AE information should begin at initiation of study treatment until 
the  follow-up  contact,  at  the  time points  specified  in  the  Schedule  of  Activities  (Section 2). 
Nonserious AE information should also be collected from the start of a placebo lead-in period or 
other observational period intended to establish a baseline status for the participants.
Sections  5.6.1  and  5.6.2  in  the  Investigator  Brochure  (IB)  represent  the  Reference  Safety 
Information  to  determine  expectedness  of  serious  adverse  events  for  expedited  reporting. 
Following the participant’s written consent to participate in the study, all SAEs, whether related 
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or  not  related  
to  study  drug,  must  be  collected,  
including  
those  
thought  
to  be  associated  with 
protocol-specified procedures.
All  SAEs  must  be  collected  that occur  during  the  screening  period  and  within 100  days  of 
discontinuation of dosing. If applicable, SAEs must be collected that relate to any later protocol-
specified procedure (e.g., a follow-up skin biopsy).
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure.
• Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF section.
• All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 9. 
• The investigator will submit any updated SAE data to the sponsor within 24 hours of this being 
available.
Investigators  are  not  obligated  to  actively  seek  AEs  or  SAEs  in  former  study  participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor.
The  method  of  evaluating,  and  assessing  causality  of  AEs  and  SAEs  and  the  procedures  for 
completing and reporting/transmitting SAE reports are provided in Appendix 9.
9.2.1.1  Adverse Events of Special Interest – Immune-mediated AEs 
Immune-mediated AEs (IMAEs) are specific events (or groups of PTs describing specific events) 
that  
include  pneumonitis,  diarrhea/colitis,  hepatitis,  nephritis/renal  dysfunction,  
rash,  endocrine 
(adrenal  insufficiency,  hypothyroidism/thyroiditis,  hyperthyroidism,  diabetes  mellitus,  and 
hypophysitis),  and  other  specific  events,  considered  as  potential  immune-mediated  events  by 
investigator, that meet the definition summarized below: 
• those occurring within 100 days of the last dose 
• regardless of causality
• with no clear alternate etiology based on investigator assessment, or with an immune-mediated 
component 
• treated   with  immune-modulating   medication  (Of   note,   adrenal  insufficiency, 
hypothyroidism/thyroiditis,  hyperthyroidism,  diabetes  mellitus,  and  hypophysitis  are 
considered  
IMAEs  
regardless  of  
immune-modulating  medication  use,  since  endocrine  drug 
reactions are often managed without immune-modulating medication).
Table 9.2.1.1-1below provides a summary of the IMAEs category and their respective preferred 
terms.
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Table 9.2.1.1-1:  
Preferred Terms Included in Analysis of IMAEs to Support 
Warnings and Precautions
IMAE Category
PTs included under IMAE Category
Pneumonitis
Pneumonitis, interstitial lung disease
Diarrhea/Colitis
Diarrhea, colitis, enterocolitis
Hepatitis
Hepatotoxicity, hepatitis, hepatitis acute, autoimmune hepatitis, AST 
increased, ALT increased, bilirubin increased, ALP increased
Adrenal insufficiency
Adrenal insufficiency
Hypothyroidism/Thyroiditis
Hypothyroidism, thyroiditis
Thyroiditis acute (collapsed with thyroiditis for frequency), Autoimmune 
thyroiditis (collapsed with thyroiditis for frequency)
Hyperthyroidism
Hyperthyroidism
Hypophysitis
Hypophysitis
Diabetes mellitus
Diabetes mellitus, diabetic ketoacidosis
Nephritis and renal dysfunction
Nephritis, nephritis allergic, tubulointerstitial nephritis, acute renal failure, 
renal failure, increased creatinine
Rash
Rash, rash maculopapular
9.2.2  
Method of Detecting AEs and SAEs
Adverse  events  can  be  spontaneously  reported  or  elicited  during  open-ended  questioning, 
examination, or evaluation of a participant. (In order to prevent reporting bias, participants should 
not be questioned regarding the specific occurrence of one or more AEs.)
9.2.3  
Follow-up of AEs and SAEs
• Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 9).
• Follow-up  
is  also  
required  
for nonserious  AEs  
that  cause  
interruption  or  discontinuation  of 
study treatment and for those present at the end of study treatment as appropriate.
•  All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at  subsequent  visits/contacts.  All  SAEs,  and  non-serious  AEs  of  special  
interest  
(as  defined  
in 
Section  9.2will  be  followed  until  resolution,  until  the  condition  stabilizes,  until  the  event  is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 9.
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9.2.4  
Regulatory Reporting Requirements for SAEs
• Prompt  notification  by  the  investigator  to  the  Sponsor  of  SAEs is  essential  so  that  legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.
• An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will file it along with 
the  Investigator’s  Brochure  and  will  notify  the IRB/IEC,  if  appropriate  according  to  local 
requirements.
Sponsor  or  designee  will  be  reporting  adverse  events  to  regulatory  authorities  and  ethics 
committees according to local applicable laws including European Directive 2001/20/EC and FDA 
Code  of  Federal  Regulations  21  CFR  Parts  312  and  320.  A  SUSAR  (Suspected,  Unexpected 
Serious Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory 
authorities and investigators following local and global guidelines and requirements.
All SAEs must be collected that occur during the screening period and within 100 days of the last 
dose of study treatment. For participants assigned to treatment and never treated with study drug, 
SAEs should be collected for 30 days from the date of treatment assignment.
9.2.5  
Pregnancy
If,  
following  
initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant  or  may  have  been  pregnant  at  
the  
time  of  study  exposure,  including  during  at  least
5 half-lives  after  product  administration,  the  investigator  must  immediately  notify  the  BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form 
to BMS Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Appendix 9.
In most cases, the study treatment will be permanently discontinued in an appropriate manner (e.g., 
dose tapering if necessary for participant safety). Please call the BMS Medical Monitor within 24 
hours of awareness of the pregnancy. Protocol-required procedures for study discontinuation and 
follow-up must be performed on the participant.
Follow-up  
information  
regarding  
the  course of  
the  pregnancy,  
including  perinatal  and  neonatal 
outcome  and,  where  applicable,  offspring  information  must  be  reported  on  the  Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor  or  designee.  In  order  for  Sponsor  or  designee  to  collect  any pregnancy  surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
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9.2.6  
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
• Any laboratory test result that is clinically significant or meets the definition of an SAE 
• Any  
laboratory  
test  
result  abnormality  
that  
required  
the  participant  
to  have  study  
treatment 
discontinued or interrupted
• Any  laboratory  test  result  abnormality that  required  the  participant  to  receive  specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (e.g., anemia versus low hemoglobin value).
9.2.7  
Potential Drug Induced Liver Injury (DILI)
Wherever  possible,  
timely  confirmation  of  initial liver-related  
laboratory  abnormalities  should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the  defined  criteria,  must  be  reported  as  SAEs  (see Section  9.2and Appendix  9 for  reporting 
details).
Potential drug induced liver injury is defined as: 
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3) No  other  immediately  apparent  possible  causes  of  AT  elevation  and  hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
9.2.8  
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
9.3  
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is  considered  both  excessive  and  medically  important.  All  occurrences  of  overdose  must  be 
reported as an SAE (see Section9.2).
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In the event of an overdose the investigator should:
1) Contact the Medical Monitor immediately
2) Closely monitor the participant for AEs/SAEs and laboratory abnormalities 
3) Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
Decisions  regarding  dose  interruptions  or  modifications  will  be  made  by  the  investigator  in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
9.4  
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities.
9.4.1  
Physical Examinations
Refer to Schedule of Activities.
9.4.2  
Vital signs
Refer to Schedule of Activities.
9.4.3  
Electrocardiograms
Refer to Schedule of Activities.
9.4.4  
Clinical Safety Laboratory Assessments
Investigators  must  document  
their  review  of  each  laboratory  safety  report. Please  refer  
to  
the 
Schedule of Activities in Section 2for details related to the required laboratory assessment.
9.4.5  
Imaging Safety Assessment
Any  
incidental  findings  of  potential  clinical  
relevance  
that  are  not  directly  associated  with  
the 
objectives  of  the  protocol  should  be  evaluated  and  handled  by  the  Study  Investigator  as  per 
standard medical/clinical judgment. 
 
 
 
 
 
 
 
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10 
STATISTICAL CONSIDERATIONS
10.1  
Sample Size Determination 
The sample size of the study is mainly determined by the feasibility concern. The study plans to 
enroll 200 participants, 100 in Cohort 1, 50 in Cohort 2, 25 in Cohort 3, and 25 in Cohort 4 (100 in 
Cohort  1  and  100  in  Cohorts  2-4  combined).  Enrollment  in  Cohort  1  for  participants  with  a 
favorable risk score will be capped at 25% of the total population to be enrolled in that cohort. 
In general, the combination of nivolumab and ipilimumab has higher rates in IMAE of high grade 
(Grade  3-4)  than  nivolumab  monotherapy.  Study CA209016  reports  that  both  combination 
treatment arms have approximately 40-60% high grade IMAEs (34.0% in N3+I1 arm and 63.8% 
in N1+I3 arm); study CA209012 (for NSCLC) reports approximately 35% high grade IMAEs in 
both  combined  
therapy  arms.  Given  
these  
reported  values,  
the  precision  of  half  width  of  95% 
confidence interval of AE rates is between 9.3% and 9.8% for 100 participants and between 6.6% 
and  6.9%  for 200  participants pooled  together.  These  precisions  are  deemed  as  acceptable  in 
evaluating the research hypotheses with respect to study cohorts in terms of AE rates in the range
reported by previous studies.
10.2  
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All enrolled participants: all participants who signed an informed consent 
form and were registered into the IVRS.
Treated
All treated participants: all participants who received any nivolumab. This is 
the primary population for safety and efficacy analyses. .
Response Evaluable
All response evaluable participants: all treated participants who have baseline 
and at least one on-study evaluable tumor measurement.
10.3  
Statistical Analyses
Detailed  analyses  will  be  specified  
in  
the  statistical  analysis  plan  separately.  
In  general,  unless 
expressly stated otherwise, all analyses will be performed by Cohort 1, and Cohorts 2-4 combined.
Demographics, baseline disease characteristics and baseline laboratory results will be summarized 
using descriptive statistics for all treated participants.
10.3.1  Efficacy Analyses
Endpoint  
Statistical Analysis Methods
Primary
Not applicable
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10.3.4 
Interim Analyses 
Not applicable. 
10.3.5  Final Analyses
The  
final  analysis  will  be  performed  when  all  participants  have  completed the  study treatment. 
Data cuts for publication purposes earlier than all participants complete the study are possible.
The Statistical Analysis Plan will further describe the planned analyses.
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12  
APPENDICES
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APPENDIX 1  
ABBREVIATIONS AND TRADEMARKS
Term
Definition
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AT
aminotransaminases
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
Ca++
calcium
Cavg
average concentration
CBC
complete blood count
ccRCC
Clear-cell renal cell carcinoma
CFR
Code of Federal Regulations 
CI
confidence interval
CLcr
creatinine clearance
Cmax, CMAX  
maximum observed concentration
Cmin, CMIN  
minimum observed concentration
CNS
Central nervous system
CRF
Case Report Form, paper or electronic
CR
Complete response
C1W1D1  
Cycle 1 Week 1 Day 1 
DMC
Data monitoring committee
DOR
Duration of response
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EEG
electroencephalogram
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Term
Definition
eg
exempli gratia (for example)
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
g
gram
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
Human Immunodeficiency Virus
HR
heart rate
HRQoL
Health Related Quality of Life
HRT
hormone replacement therapy
ICD
International Classification of Diseases
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMAE
Immune-mediated adverse event
IMDC
International metastatic RCC database consortium (IMDC) Prognostic 
Criteria
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
I-O
Immuno-oncology 
IRB
Institutional Review Board
IRT
Interactive Response Technology
IU
International Unit
IV
intravenous
K
slope of the terminal phase of the log concentration-time curve
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Term
Definition
K+
potassium
kg
kilogram
KPS
Karnofsky Performance Status
L
liter
LAM
Lactation amenorrhea method
LC
liquid chromatography
LDH
lactate dehydrogenase
mg
milligram
Mg++
magnesium
min
minute
mL
milliliter
mmHg
millimeters of mercury
MR
medical research
mRCC
Metastatic Renal Cell Carcinoma
MSKCC 
Memorial Sloan Kettering Cancer Center 
MTD
maximum tolerated dose
mWHO
Modified World Health Organization
μg
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
ng
nanogram
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
Non-small cell lung cancer
ORR
Objective response rate 
PBMC
Peripheral blood mononuclear cell
PD
Progressive diseases 
PFS
Progression-free survival
PK
pharmacokinetics
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Term
Definition
PR
Partial response 
RBC
red blood cell
SAE
serious adverse event
SD
standard deviation
SOP
Standard Operating Procedures
TTR
Time to Response 
ULN
Upper limit of normal
VEGF
Vascular epithelial growth factor
WBC
white blood cell
WHO
World Health Organization
WOCBP 
women of childbearing potential
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APPENDIX 2  
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study.  The term ‘Subject’ used in the eCRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:
• Good Clinical Practice (GCP), 
• as defined by the International Council on Harmonisation (ICH)
• in accordance with the ethical principles underlying European Union Directive 2001/20/EC
• United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 
• applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and  the  participant informed  consent  will  receive  approval/favorable  opinion  by  Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All  potential  serious  breaches  must  be  
reported to  Sponsor or  designee  
immediately.  A  serious
breach  
is  a  breach  of  
the  conditions  and  principles of  GCP  
in  connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity 
of the subjects of the study or the scientific value of the study.
Personnel  involved  in  conducting this  study  will be  qualified  by  education,  training,  and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from  the  IRB/IEC  for  the  protocol,  consent  form,  participant  recruitment  materials  (e.g., 
advertisements), and any other written information to be provided to subjects. The investigator or 
BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product labeling 
information to be provided to subjects and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (e.g., expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The  investigator  should  not  implement  any  deviation  or  change  to  
the  protocol  without  prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
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applicable,  also  by  local  health  authority) except  where  necessary  to  eliminate  an  immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining  
relevant  
  approval/favorable  opinion(s)  
the  deviation  or  change  will  be  submitted,  as 
soon as possible to:
• IRB/IEC for 
• Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation  of  approval/favorable  opinion  signed  by  the  chairperson  or  designee  of  the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If  an  amendment  substantially  alters  the  study  design  or  increases  the  potential  risk  to  the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators  and  sub-Investigators  will provide  
the  Sponsor  with  sufficient,  accurate  
financial 
information  
in  accordance  with  
local  
regulations  
to allow  
the  Sponsor  
to  submit  complete  and 
accurate financial  certification  or  disclosure  statements  to  the  appropriate  health  authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives (as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the participant volunteers to participate.
Sponsor or designee will provide the investigator with an appropriate (i.e., Global or Local) sample
informed  consent  form  which  will  include  all elements  required  by  ICH,  GCP  and  applicable
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Investigators must:
• Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 
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• Allow  time  necessary  for  participant  or  participant
's  legally  acceptable  representative  to 
inquire about the details of the study.
• Obtain an informed consent signed and personally dated by the participant or the participant
's 
legally  acceptable  representative  and  by  the  person  who  conducted  the  informed  consent 
discussion. 
• Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise  the  informed  consent  whenever  important  new  information becomes  available  that  is 
relevant to the participant
's consent. The investigator, or a person designated by the investigator, 
should  
fully  
inform the participant or the participant
's  
legally acceptable representative or legal 
guardian,  of  all  pertinent  aspects  of  the  study  and  of  any  new information  relevant  to  the 
participant
's  willingness  
to  continue  participation  
in  
the  study.  This  communication  should  be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects
' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
Subjects unable to give their written consent (e.g., stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The participant 
must  also  be  informed  about  
the  nature  of  
the  study  
to  
the  extent  compatible  with  his  or  her 
understanding, and should this participant become capable, he or she should personally sign and 
date the consent form as soon as possible. The explicit wish of a participant who is unable to give 
his or her written consent, but who is capable of forming an opinion and assessing information to 
refuse participation in, or to be withdrawn from, the clinical study at any time should be considered 
by the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
SOURCE DOCUMENTS
The  Investigator  is  responsible  for  ensuring  that the  source  data  are  accurate,  legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or  transmitted  electronically  via  computerized  systems  (and/or  any  other  kind  of  electronic 
devices)  as  part  of  regulated  clinical  trial  activities,  such  systems  must  be  compliant  with  all 
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applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse  event  tracking/reporting,  protocol  required  assessments,  and/or  drug  accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities,  such  paper  
records  should  be  certified  copies.  A  certified  copy  consists  of  a  copy  of 
original  
information  
that  has  been  verified,  as  
indicated  by  a dated  signature,  as  an  exact  copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study  
treatment integrity  and  
traceability from  
receipt,  preparation,  administration,  and  
through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
If
Then
Supplied by BMS (or its vendors):
Records or logs  must comply with applicable 
regulations and guidelines and should include:
• amount received and placed in storage 
area
• amount currently in storage area
• label identification number or batch 
number
• amount dispensed to and returned by each 
participant, including unique participant
identifiers
• amount transferred to another area/site for 
dispensing or storage
• nonstudy disposition (e.g., lost, wasted) 
• amount destroyed at study site, if 
applicable
• amount returned to BMS
• retain samples for 
bioavailability/bioequivalence, if 
applicable 
• dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
Sourced by site, and not supplied by  BMS or 
its vendors (examples include IP sourced from 
the  sites  stock  or  commercial  supply,  or  a 
specialty pharmacy)
The  investigator   or   designee   accepts 
responsibility for documenting traceability and 
study  drug  integrity  in  accordance  with 
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If
Then
requirements  applicable  under  law  and  the 
SOPs/standards of the sourcing pharmacy.   
These records should include:
• label identification number or batch 
number 
• amount dispensed to and returned by each 
participant, including unique participant 
identifiers
• dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
BMS  or  designee  will  provide  forms  to  facilitate inventory  control  if  the  investigational  site  does not  have  an 
established system that meets these requirements.
CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or  entered  as  a  control  in  
the  
investigation.  Data  
that  are  derived  from  source  documents  and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For  sites  using  the  Sponsor  or  designee electronic  data  capture tool,  electronic  CRFs  will  be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be  reported  on  the  electronic  SAE  form  and  Pregnancy  Surveillance  form,  respectively.    If 
electronic SAE form is not available, a paper SAE form can be used. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. The  investigator  must  retain  a  copy  of  the  CRFs  including records  of  the  changes  and 
corrections.
Each  
individual electronically signing electronic  CRFs  must  meet Sponsor or designee training 
requirements  and  must only  access  
the  BMS  electronic  data  capture tool  using  
the  unique  user 
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account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
MONITORING
Sponsor  or  designee representatives  will  review  data  centrally  to  identify  potential  issues  to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities  
remain  acceptable. Certain  CRF  pages  and/or  electronic  
files  may  serve  as  
the  source
documents:
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee.
RECORDS RETENTION
The  investigator  (or  head  of  
the  study  site  in  Japan)  must  retain  all  study  records  and  source 
documents  for  the  maximum  period  required by  applicable  regulations  and  guidelines,  or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If  
the  
investigator  withdraws  from  
the  study  
(e.g.,  
relocation,  
retirement),  
the  
records  shall  be 
transferred to a mutually agreed upon designee (e.g., another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If..
Then
Study treatments supplied by BMS (including 
its vendors
Any unused study treatments supplied by BMS 
can  only  be  destroyed  after  being  inspected 
and  reconciled  by  the  responsible  Study 
Monitor  unless  study  treatments  containers 
must be immediately destroyed as required for 
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Then
safety,  or  to  meet  local  regulations  (e.g., 
cytotoxics or biologics).
If study treatments will be returned, the return 
will  be  arranged  by  the  responsible  Study 
Monitor.
Study treatments sourced by site, not supplied 
by  BMS  (or  its  vendors)  (examples  include 
study  
treatments  sourced from  
the  sites  stock 
or  commercial  supply,  or  a  specialty 
pharmacy)
It  is  the  investigator’s  or  designee’s 
responsibility  to  dispose  of  all  containers 
according  to  the  institutional  guidelines  and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for  proper  disposal  have  been established  according  to  applicable  federal,  state,  local,  and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:
• On-site disposal practices must not expose humans to risks from
 the drug.
• On-site  disposal  practices  and  procedures  are  in  agreement  with  applicable  laws  and 
regulations, including any special requirements for controlled or hazardous substances.
• Written procedures for on-site disposal are available and  
followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
• Records  are  maintained  that allow  for  traceability  of  each  container,  including  the  date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method  of  disposal,  i.e.,  incinerator,  licensed  sanitary  landfill,  or  licensed  waste  disposal 
vendor must be documented.
• Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for  return  of  study treatments  provided  by  BMS  (or  its  vendors).  Destruction  of  non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
CLINICAL STUDY REPORT AND PUBLICATIONS
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:
• External Principal Investigator designated at protocol development
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• National Coordinating Investigator 
• Study Steering Committee chair or their designee
• Participant recruitment (e.g., among the top quartile of enrollers)
• Involvement in trial design
• Regional  representation  (e.g.,  among  top  quartile  of  enrollers  from  a  specified  region  or 
country)
• Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTA) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor  or  designee  at  the  earliest  practicable  time  prior  to  submission  or  presentation  and 
otherwise within the time period set forth in the CTA.
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APPENDIX 3  
RENAL CELL CARCINOMA: HISTOLOGY DEFINITIONS
Clear Cell Renal Cell Carcinoma
1) Definition
• Carcinoma of the kidney composed predominantly of nests and sheets of clear cells 
2) Alternate/Historical Names
• Conventional type renal cell carcinoma 
• One of several different neoplasms previously diagnosed as granular cell renal cell carcinoma 
(some cases) 
3) Diagnostic Criteria
• Grossly circumscribed mass 
− Frequently hemorrhagic and necrotic 
− Soft yellow areas frequent, alternating with fibrous to mucoid areas 
♦ May appear necrotic but frequently are viable 
− Multifocal in about 5% of cases 
♦ More frequent in familial cases
• Sheets and nests of cells surrounded by extensive capillary network 
− Frequently forms alveolar lumens 
♦ No lumenal border differentiation 
♦ Frequently dilates to form micro- and macrocystic pattern 
− If exclusively cystic, see multilocular cystic renal cell carcinoma
♦ Lumens may contain eosinophilic proteinaceous fluid or RBCs
− Tubular and papillary foci rare 
♦ Consider clear cell tubulopapillary carcinoma if present 
• Predominantly composed of clear cells 
− Higher  grade  tumors  often  lose  clear  cell  cytoplasm  but  may  still  have  underlying 
recognizable low grade clear cell areas 
− Frequent granular eosinophilic areas 
♦ Rarely predominant 
♦ If extensively granular and eosinophilic, consider oncocytoma
− Sharp cell borders 
− Cytoplasm contains lipid and glycogen 
− Features reported in rare cases 
♦ Rhabdoid cells in 5% of cases 
o Abundant eccentric cytoplasm containing large eosinophilic inclusions 
o Eccentric large round nuclei, may be multinucleate 
o Keratin, EMA, vimentin positive 
o 25% of cases with rhabdoid areas have sarcomatoid areas 
♦ Eosinophilic 5-7 mm hyaline globules 
♦ Basophilic inclusions 
♦ Myospherulosis 
♦ Coarse brown granular pigment 
♦ Melanin 
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• Nuclei range from round and regular at low grade to pleomorphic at high grade 
− Nuclear features and nucleolar size incorporated into grading 
• Dysplasia of adjacent non-carcinomatous tubules has been reported 
• Multiple and/or familial clear cell carcinomas may be seen in von Hippel Lindau syndrome
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Xp11 / TFE3 Translocation Carcinoma of the Kidney
1)Definition
• Renal  carcinoma  comprising  a  
large  
fraction  of  renal  carcinomas  occurring  
in  young 
patients  and  associated  with  translocations  involving  the  TFE3 gene  at  chromosome 
Xp11.2 
2) Alternate/Historical Names
• Juvenile renal cell carcinoma 
3) Diagnostic Criteria
• Most cases reported in children and young adults, mean age 25 years 
− Under-recognized in adults 
♦ Two studies find an incidence of 1-5% in adults 
♦ If possible, fresh tumor tissue should be sent for cytogenetics in all renal tumor patients 
under 40 years of age and in older patients in which an unusual tumor is discovered at 
frozen section 
• Composed of cells with abundant to voluminous cytoplasm
− Clear to granular eosinophilic cytoplasm 
− Sharp cell borders 
• Pleomorphic and polymorphic growth patterns 
− Frequent papillary, pseudopapillary, alveolar and nested patterns 
− Clusters of small cells centered on hyaline cores may be seen 
♦ Collections of small cells should suggest a t(6;11) carcinoma 
− Patterns and cells may vary according to the precise translocation involved 
• Large vesicular nuclei 
− Prominent round nucleoli 
− Mitotic figures frequent 
• Features frequently present 
− Psammoma bodiesmay be abundant 
− Intracytoplasmic hyaline droplets 
• Melanocytic variant has been reported 
• Presence of Xp11 translocation by classical cytogenetics, PCR or FISH 
− Demonstration may not be required in every case 
− TFE3  immunohistochemistry  may  be  less  reliable  than  reported  in  the  literature  with 
numerous false positives 
− Lack  of,  or  minimal,  cytokeratin  and  EMA  expression may  be  the  most  helpful 
immunophenotypic findings 
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Chromophobe Renal Cell Carcinoma
1) Definition
• Carcinoma of the kidney composed predominantly of distinctive cells with prominent cell 
membranes and cleared cytoplasm 
1) Alternate/Historical Names
• Conventional type renal cell carcinoma (some cases) 
• Granular cell renal cell carcinoma (some cases) 
2) Diagnostic Criteria
• Generally sheet-like or broad alveolar patterns 
− Less frequently tubular or cystic 
− Vessels frequently thick walled and/or eccentrically hyalinized 
• Composed of cells with cytoplasm ranging from clear to eosinophilic 
− Clear cells (classical) have abundant clear cytoplasm 
♦ May be flocculent or "soap bubble" 
♦ Prominent, distinct cell membrane 
− Eosinophilic  (variant)  cells  have  moderate  amount  of  finely  granular  eosinophilic 
cytoplasm 
♦ Prominent perinuclear clearing 
o Peripheral condensation of cytoplasm accentuates cell membrane 
− Nuclei vary from round, regular to koilocytoid 
♦ Koilocytoid nuclei have wrinkled nuclear membrane, coarse chromatin 
♦ Frequently binucleate 
− Most often mixed but may be pure of either type 
♦ Mixed cases frequently have a distinctive pattern
o Eosinophilic cells occupy the center of the nest, merging with 
o Peripheral clear cells with abundant cytoplasm adjacent to the fibrovascular stromal 
border 
• Prominent cell borders with centrally located nuclei with perinuclear clearing result in a 
"plant cell appearance" 
− Reminiscent of the rigid cell walls of plant cells 
• Hale colloidal iron stain positive 
− A temperamental stain 
− Other colloidal iron stains are not equivalent 
• Chromophobe  and hybrid  chromophobe/oncocytoma  cases  may  be  seen  
in  Birt  Hogg  Dubé 
syndrome
− Sporadic hybrid chromophobe/oncocytoma cases have been described (Petersson) 
• Sarcomatoid cases may have a variety of patterns (Viswanathan; Quiroga-Garza) 
− Poor prognosis 
• One case reported with neuroendocrine differentiation (Parada) 
− Not clear from the report that this was not a collision tumor
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Papillary Renal Cell Carcinoma
1) Definition
• Carcinoma of the kidney with a predominantly papillary growth pattern 
Covered separately (as discrete entities)
• Clear cell tubulopapillary carcinoma 
• Papillary oncocytoma 
• Xp11 translocation carcinoma 
2) Diagnostic Criteria
Predominantly papillary pattern 
• May have tubular areas 
• Papillae have fibrovascular cores 
• May be intracystic 
• Rare cases of apparent solid pattern 
− Formed by collapsed tubules and papillae 
Two types, have been defined by the types of cells lining papillae and tubules 
• We do not routinely classify papillary carcinomas according to type 
− In our experience, many cases show a mixed pattern or do not clearly conform to either of 
these types 
• Nevertheless, familial cases associated with MET mutations tend to show a type 1 morphology 
whereas those associated with fumarate hydratase mutations tend to show a type 2 morphology 
Type 1 is lined by small cells with clear to basophilic cytoplasm 
• Single layer of small oval nuclei 
− Inconspicuous nucleoli 
• Frequent findings 
− Foamy macrophages and/or edema in papillary cores 
− Psammoma bodies and calcium oxalate crystals 
− Glomeruloid papillae 
♦ Most cases low grade (1 or 2)and low stage 
Type 2 is lined by large cells with abundant eosinophilic cytoplasm 
• If cytoplasm is extensively granular, consider papillary oncocytoma, see Differential Diagnosis 
• Nuclei frequently pseudostratified or apical 
• Large spherical nuclei 
− Prominent nucleoli 
• Macrophages, edema, psammoma bodies, glomeruloid papillae infrequent 
• Most cases high grade (3), many higher stage 
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Papillary carcinoma with low grade spindle cell features has been described (Argani) 
• Predominantly solid 
− 4 of 5 reported cases had papillary areas 
− All appear to be Type 1 
• Nuclear grade 2 
• Lacks mucinous stroma of mucinous tubular and spindle cell carcinoma 
− May be distinguishable only by FISH for trisomy 7 or 17 
• If under 0.5 cm and grade 1 or 2, designate as papillary adenoma
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Carcinoma of the Collecting Ducts of Bellini
1) Definition
• High grade renal adenocarcinoma arising in medulla of the kidney, with a predominantly 
invasive tubular growth pattern
• Clearly  overlaps   morphologically  and  immunophenotypically   withmedullary 
carcinomabut the latter has a distinctive clinicopathologic setting
2) Alternate/Historical Names
• Bellini duct carcinoma
• Collecting duct carcinoma
3) Diagnostic Criteria
• Metastatic adenocarcinoma must be ruled out in every case
− Collecting duct carcinoma should be considered a diagnosis of exclusion
• Firm mass centered on the renal medulla
− Frequently extends into renal cortex and/or pelvis
• Infiltrating tubular or tubulopapillary pattern
− Occasionally solid or microcystic
− Usually single layer of lining cells with hobnail nuclei
− Extra-renal and vascular invasion frequent
− Cytoplasmic mucin may be present
♦ Signet ring cells seen in rare cases
− Rare sarcomatoid cases
♦ Defined  by  presence  of  a  distinct  spindle  cell  component  occupying  at  least  one 
microscopic low-power field (×40) 
• Prominent stromal desmoplasia
− Frequent mixed acute and chronic inflammation
• High grade nuclear atypia
− Equivalent to Fuhrman 3 or 4
− Frequent mitotic figures
− Dysplastic epithelial lining frequently seen in adjacent collecting duct
• Cases described as low grade collecting duct carcinomas in the past are better classified as one 
of the following
− Mucinous tubular and spindle cell carcinoma
− Tubulocystic carcinoma
• Renal medullary carcinomais considered a separate entity
− Considered by some reports to be a variant of collecting duct carcinoma
− Overlaps histopathologically with collecting duct carcinoma but is separated based on the 
following features
♦ Occurrence in young patients
♦ Association with sickle cell trait
♦ Lack of INI1 expression (Cheng 2008) vs retention in 85% of collecting duct carcinoma 
(Elwood 2011)
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Renal Medullary Carcinoma
4) Definition
• High grade renal adenocarcinoma arising in medulla of the kidney, associated with sickle 
cell trait
5) Alternate/Historical Names
• In the past, some were included incollecting duct carcinoma
− Distinction may be largely clinical 
6) Diagnostic Criteria
• Essentially every case associated with sickle cell trait or sickle cell disease
− Sickled cells may be seen in adjacent vessels
− Nearly all of African ancestry
• Firm mass centered on the renal medulla
− Frequently extends into renal cortex and/or pelvis
• Infiltrating sheets or cords of cells
− Frequent reticular/microcystic pattern
♦ Spaces of varying size
♦ Reminiscent of yolk sac tumor
♦ May also have tubular and papillary patterns
− Dark eosinophilic granular cytoplasm
− Intralumenal mucin frequent
− Extra-renal and vascular invasion frequent
• Rhabdoid pattern may be seen
− INI1 negative (all patterns)
• Prominent stromal desmoplasia
− May be collagenous or myxoid
• High grade nuclear atypia
− Pleomorphic vesicular nuclei with large nucleoli
− Frequent mitotic figures
− Frequent necrosis and hemorrhage
♦ May form microabscesses
• Renal medullary carcinoma is considered a separate entity fromcollecting duct carcinoma
− Considered by some reports to be a variant of collecting duct carcinoma
− Overlaps histopathologically with collecting duct carcinoma but is separated based on the 
following features
♦ Occurrence in young patients
♦ Association with sickle cell trait
♦ Lack of INI1 expression (Cheng 2008) vs retention in 85% of collecting duct carcinoma 
(Elwood 2011)
http://surgpathcriteria.stanford.edu/kidney
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APPENDIX 4  
RECIST 1.1 GUIDELINES
1  
EVALUATION OF LESIONS
At  baseline,  
tumor  lesions/lymph  nodes  will  be categorized  measurable  or  non-measurable  as 
follows:
1.1  
Measurable
Tumor lesions: Must be accurately  measured  
in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
1. 10 mm by CT scan (CT scan slice thickness no greater than 5 mm)
2. 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable)
3. 20 mm by chest x-ray
Malignant lymph nodes:To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm).
Lymph  nodes  merit special  mention since they  are normal anatomical structures which  may  be 
visible  by  imaging  even  if  not  involved  by  tumor.  Pathological nodes  which  are  defined  as 
measurable  and  may  be  identified  as  
target  lesions  must  meet  
the  criterion  of  a  short  axis  of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the image 
is obtained (for CT scan this  
is almost always the axial plane;  
for MRI the plane of acquisition 
may be axial, saggital or coronal). The smaller of these measures is the short axis. For example, 
an abdominal  node which  
is reported as being 20 mm  x 30  mm  has a short axis of 20 mm  and 
qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) should 
be  considered  non-target  lesions.  Nodes  that  have  a  short  axis <  10  mm  are  considered 
non-pathological and should not be recorded or followed.
1.2  
Non-Measurable
All  other  lesions  are  considered  non-measurable,  including  small  lesions  (longest  diameter 
< 10mm  or  pathological  lymph  nodes  with ≥10  to  <  15  mm  short  axis)  as  well  as  truly 
non-measurable  lesions.  Lesions  considered  truly  non-measurable  include:  leptomeningeal 
disease,  ascites,  pleural  or  pericardial  effusion,  inflammatory  breast  disease,  lymphangitic 
involvement of skin or lung, abdominal  masses/abdominal organomegaly  
identified by physical 
exam that is not measurable by reproducible imaging techniques.
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2  
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be  identified  as  target  lesions  and  will  be  recorded  and  measured  at  baseline  (this  means  in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative  of  all  involved  organs,  but  in  addition  should  be  
those  
that  
lend  
themselves  
to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will  be calculated and reported as the baseline sum diameters. If  
lymph  nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target  
lesions  and  should  also  be  
recorded  at  baseline.  Measurements  are  not  
required  and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple nontarget lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
3  
RESPONSE CRITERIA
3.1  
Evaluation of Target Lesions
Complete  Response  
(CR):Disappearance  of  all  
target  
lesions.  Any  pathological  
lymph  nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
Partial Response (PR):At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters.
Progressive Disease (PD):At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest  on  study).  
In  addition  
to the  
relative  
increase  of  20%,  
the  sum  must  also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression).
Stable  Disease  (SD):Neither  sufficient  shrinkage  
to  qualify  for  PR  nor  sufficient  increase  
to 
qualify for PD, taking as reference the smallest sum diameters while on study.
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3.1.1  
Special Notes on the Assessment of Target Lesions
3.1.1.1  Lymph nodes
Lymph nodes  
identified as target lesions should always  have the actual short axis  measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods  may  
therefore  be  designed  
to  have  
target  nodal  
lesions recorded  
in  a  separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
3.1.1.2  Target lesions that become ‘too small to measure’
While on study, all  
lesions (nodal  and non-nodal) recorded at baseline should  have their actual 
measurements  recorded  at each  subsequent  evaluation,  even  when very  small  (eg, 2  mm). 
However,  sometimes  lesions  or  lymph  nodes  which  are  recorded  as  
target  lesions  at  baseline 
become  so  faint  on  CT  scan  
that  
the  radiologist  may  not  feel  comfortable  assigning  an  exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
(Note: It is less likely that this rule will be used for lymph nodes since they usually have a definable 
size when normal and are frequently surrounded by fat such as in the retroperitoneum; however, 
if a lymph node is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned in this circumstance as well). This default value is derived from 
the 5 mm CT slice thickness (but should  not be changed with varying CT slice thickness). The 
measurement  of  these  lesions  is  potentially non-reproducible,  therefore  providing  this  default 
value  will  prevent  
false  
responses  or  progressions  based  upon  measurement  error.  To  
reiterate, 
however, if the radiologist is able to provide an actual measure, that should be recorded, even if it 
is below 5 mm.
3.1.1.3  Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them  may  be  maintained  
that  would  aid  
in  obtaining  maximal  diameter  measurements  of  each 
individual  
lesion. If the lesions  have truly coalesced such that they are no longer separable, the 
vector  of  
the  
longest  diameter  
in this  
instance  should  be  
the  maximal  
longest  diameter  
for  
the 
‘coalesced lesion’.
3.2  
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
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not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.
Complete Response (CR):Disappearance of all  non-target lesions and  normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10mm short axis). 
Non-CR/Non-PD:Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD):Unequivocal progression (see comments below) of existing non-target 
lesions.  (Note:  the  appearance  of  one  or  more  new  lesions  is  also  considered 
progression).
3.2.1  
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
3.2.1.1  When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in presence 
of  SD  or  PR  in  target  disease,  the  overall  tumor  burden  has  increased  sufficiently  to  merit 
discontinuation  of  
therapy  (see  examples  in Appendix  2  and  further  details  below).  A  modest 
‘increase’  
in  
the  size  of  one  or  more  non-target  
lesions is  usually  not  sufficient  
to  qualify  for 
unequivocal  progression  status.  The  designation  of  overall progression  solely  on the  basis  of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.
3.2.1.2  When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 73% 
increase  
in  
‘volume’  
(which  
is  equivalent  
to  a  20%  
increase  diameter  
in  a  measurable  
lesion). 
Examples  include  an  increase  in  a  pleural  effusion  from  ‘trace’  to  ‘large’,  an  increase  in 
lymphangitic disease from localized to widespread, or may be described in protocols as ‘sufficient 
to  require  a  change  in  therapy’.  If  ‘unequivocal  progression’  is  seen,  the  patient  should  be 
considered to have had overall PD at that point. While it would be ideal to have objective criteria 
to apply to non-measurable disease, the very nature of that disease makes it impossible to do so; 
therefore the increase must be substantial.
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3.2.2  
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new  
radiographic  
lesions;  however,  
the  
finding  of  a  new  
lesion should  be  unequivocal:  
ie,  not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone  
lesions  may  be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who  has  visceral  disease  at  baseline  and  while on  study  has  a  CT or  MRI  brain  ordered  which 
reveals  metastases.  The  patient’s  brain  metastases  are  considered  
to  be  evidence  of  PD  even  
if 
he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely 
a new lesion, then progression should be declared using the date of the initial scan. While FDG-
PET response assessments need additional study, it is sometimes reasonable to incorporate the use 
of  FDG-PET  scanning  
to  complement  CT  scanning  in  assessment  of progression  (particularly 
possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed  by CT, this  
is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
3.3  
Response Assessment
3.3.1  
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
the  end  of  
treatment  
taking  into  account  any  requirement  for  confirmation.  The  patient’s  best 
overall response assignment will depend on the findings of both target and non-target disease and 
will  also take into consideration the appearance of  new  
lesions. Furthermore, depending on the 
nature of the study and the protocol requirements, it may also require confirmatory measurement.
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3.3.2  
Time Point Response
It is assumed that at each protocol specified time point, a response assessment occurs. Table 3.3.2-
1provides a summary of the overall response status calculation at each time point for patients who 
have  measurable disease at baseline.  When patients have non-measurable (therefore non-target) 
disease only, Table 3.3.2-2is to be used. 
Table 3.3.2-1:  
Time Point Response: Patients With Target (+/- Non-Target) 
Disease
Target Lesions  
Non-Target Lesions  
New Lesions 
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
Table 3.3.2-2:  
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
a Non-CR/non-PD  is  preferred  over  SD  for  non-target  disease  since  SD  is  increasingly  used  as  endpoint  for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
3.3.3  
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
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≥4 weeks later. In this circumstance, the best overall response can be interpreted as in Table 3.3.3-
1.
Special note on response assessment:When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate  progression  should  
it  be  based  on  
increase  
in  size  of the  nodes.  As  noted  earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF).
Table 3.3.3-1:  
Best Overall Response (Confirmation of CR&PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
BEST Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD durationbmet, 
otherwise, PD
CR
PD
SD provided minimum criteria for SD durationbmet, 
otherwise, PD
CR
NE
SD provided minimum criteria for SD durationbmet, 
otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD durationbmet, 
otherwise, PD
PR
NE
SD provided minimum criteria for SD durationbmet, 
otherwise, NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
b Minimum criteria for SD duration is 6 weeks.
3.3.4  
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must  be  confirmed  by  consecutive repeat  assessments  that  should  be  performed  no  less  than 
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28 days  after  the  criteria  for  response  are  first  met.  For  
this study,  the  next  scheduled  tumor 
assessment can meet this requirement.
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial  scan.  If  repeat  scans  do  not  confirm  PD,  then  the  subject  is  considered  to  not  have 
progressive disease.
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APPENDIX 7  
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
WOMAN OF CHILDBEARING POTENTIAL (WOCBP)
A woman  
is considered  
fertile  
following  menarche and until  becoming post-menopausal unless 
permanently  sterile.  Permanent  sterilization  methods  include  hysterectomy,  bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
• Premenarchal
• Premenopausal female with 1 of the following:
− Documented hysterectomy
− Documented bilateral salpingectomy
− Documented bilateral oophorectomy
Note: Documentation  can  come  from the  site  personnel’s  
review  of  
the  participant’s  medical 
records, medical examination, or medical history interview.
• Postmenopausal female
− A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females under 
the  age  of  55  years  must  have  a  serum  follicle  stimulating hormone,  
(FSH)  
level  >  40 
mIU/mL to confirm menopause.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and  until  the  end  of  relevant  systemic  exposure,  defined  as  5  months  after  the  end  of  study 
treatment.
Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation
b 
− oral 
− intravaginal 
−transdermal 
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• Progestogen-only hormonal contraception associated with inhibition of ovulationb 
− oral 
−injectable 
Highly EffectiveMethods That Are User Independent
• Implantable  progestogen-only  hormonal  contraception  associated with  inhibition  of 
ovulationb
• Intrauterine device (IUD)
c
• Intrauterine hormone-releasing system (IUS)
c
• Bilateral tubal occlusion
• Vasectomizedpartner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
• Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
• It is not necessary to use any other method of contraception when complete abstinence  
is 
elected. 
• WOCBP  participants who  choose  complete  abstinence  must  continue to  have  pregnancy 
tests, as specified in Section 2. 
• Acceptable  alternate  methods  of  highly  effective  contraception must  be  discussed  in  
the 
event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence that 
the  IMP  and  other  study  medications  will  not  alter  hormonal  exposures  such  that  contraception  would  be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative methods 
of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Unacceptable Methods of Contraception
• Male or female condom with or without spermicide.  Male and female condoms cannot 
be used simultaneously
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• Diaphragm with spermicide
• Cervical cap with spermicide
• Vaginal Sponge with spermicide
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
• Periodic abstinence (calendar, symptothermal, post-ovulation methods)
• Withdrawal (coitus interruptus).
• Spermicide only
• Lactation amenorrhea method (LAM)
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.
• Inform  any  and  all  partner(s)  of  
their  participation  
in  a  clinical  drug  study  and  
the  need  
to 
comply with contraception instructions as directed by the investigator.
• Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 7 months after the end of study treatment.
• Female  partners  of  males  participating  
in  
the  study  
to  consider  use  of  effective  methods  of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end of 
treatment in the male participant.
• Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile  vaginal  
intercourse  or  use  a  male  condom  during  each  episode  of  penile  penetration 
during the treatment and until 7 months after the end of study treatment.
• Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting
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APPENDIX 8  
MANAGEMENT ALGORITHIMS
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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APPENDIX 9  
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study drug and 
that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study drug, whether or not 
considered related to the study drug.
All nonserious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following discontinuation 
of study treatment.
Every adverse event must be assessed by the investigator with regard to whether it is considered 
immune-mediated. For events which are potentially immune-mediated, additional information will 
be collected on the participant’s case report form.
SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event;  
it does not refer to an event which  hypothetically  might have caused death  
if  
it 
were more severe)
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Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
o a visit to the emergency room or other hospital department < 24 hours, that does 
not  result  in  admission  (unless  considered  an  important  medical  or  life-
threatening event)
o elective surgery, planned prior to signing consent
o admissions as per protocol for a planned medical/surgical procedure
o routine  health  assessment  requiring  admission  for  baseline/trending  of  health 
status (e.g., routine colonoscopy)
o medical/surgical admission other than to remedy ill health and planned prior to 
entry into the study. Appropriate documentation is required in these cases
o admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (e.g., lack of housing, 
economic  inadequacy,  caregiver  respite,  family  circumstances,  administrative 
reason)
o admission  
for administration of anticancer therapy  
in the absence of any other 
SAEs 
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening  or  result  in  death  or  hospitalization  but,  based  upon  appropriate  medical  and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home  for  allergic  bronchospasm;  blood  dyscrasias  or  convulsions  that  do  not  result  in 
hospitalization.)  Potential  drug  induced  liver  injury  (DILI)  is  also  considered  an  important 
medical event. (See Section 9.2.7for the definition of potential DILI.) 
Suspected transmission of an  
infectious agent (e.g., pathogenic or nonpathogenic) via the study 
treatment is an SAE. 
Although  pregnancy,  overdose,  cancer,  and  potential  drug  induced  liver  injury  (DILI)  are  not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 9.2.5 
for reporting pregnancies).
All SAEs must be collected that occur during the screening period and within 100 days of the last 
dose of study treatment. For participants randomized/assigned to treatment and never treated with 
study drug, SAEs should be collected for 30 days from the date of treatment assigment.
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EVALUATING AES AND SAES
Assessment of Causality
The causal relationship to study drug is determined by a physician and should be used to 
assess all adverse events (AE). The causal relationship can be one of the following:
Related:  There  is  a  reasonable  causal  relationship  between  study  drug 
administration and the AE.
Not  related:  There  is  not  a  reasonable  causal  relationship  between  study  drug 
administration and the AE. 
The  term  "reasonable  causal  relationship"  means  
there  is  evidence  to  suggest  a  causal 
relationship. 
Follow-up of AEs and SAEs
If  only  limited  information  is  initially  available,  follow-up  reports  are  required.  (Note: 
Follow-up SAE reports must include the same investigator term(s) initially reported.) 
If  an  ongoing  SAE  changes  in  its  intensity  or  relationship  to  study  drug  or  if new 
information becomes available, the SAE report must be updated and submitted within 24 
hours to BMS (or designee) using the same procedure used for transmitting the initial SAE 
report.
All SAEs must be followed to resolution or stabilization.
REPORTING OF SAES TO SPONSOR OR DESIGNEE
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• SAEs, whether related or not related to study drug, and pregnancies must be reported 
to BMS (or designee) within 24 hours of awareness of the event.
• SAEs  must  be  recorded  on  the  SAE  Report  Form;  pregnancies  on  a Pregnancy 
Surveillance Form (electronic or paper forms).
• The preferred method for SAE data reporting collection is through the eCRF.
• The paper SAE/pregnancy  surveillance  
forms are only  
intended as a  back-up option 
when the eCRF system is not functioning.
o In this case, the paper forms are to be transmitted via email or confirmed 
facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission 
is the required method for reporting. In the event the electronic system is unavailable for 
transmission, paper forms must be used and submitted immediately. When paper forms are 
used, the original paper forms are to remain on site.
SAE Telephone Contact(required for SAE and pregnancy reporting): Refer to Contact 
Information list
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SAP_001.pdf: 
Statistical Analysis Plan for 
 
Official Title of Study 
PHASE 3B/4 SAFETY TRIAL OF NIVOLUMAB COMBINED WITH IPILIMUMAB IN 
SUBJECTS WITH PREVIOUSLY UNTREATED, ADVANCED OR METASTATIC RCC 
NCT02982954 
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Statistical Analysis Plan
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DOCUMENT HISTORY
Document 
Date of Issues 
Summary of Changes
Version 1
16-Mar-2017 
Original Issue
Version 2.0
09-Aug-2018
• updated statistical analyses general 
method to state that all analyses will 
be performed by separated Cohort 1, 
Cohort 2, Cohort 3 and Cohort 4.
• added additional populations - All 
Intermediate/Poor Risk Subjects, All 
Favorable Risk Subjects and PD-L1 
treated subjects
• updated IMDC prognostic criteria to 
<80% as per protocol and also 
replaced randomization with 
treatment. 
• added additional baseline 
characteristics - IMDC prognostic 
score, KPS, time from diagnosis to 
date of first dose, Hemoglobin,
Corrected calcium, absolute 
neutrophils count, platelet count, 
histological subtypes
• updated Efficacy section 7.5 to add 
additional analyses for All 
Intermediate/Poor Risk Subjects, All 
Favorable Risk Subjects
• added section for Subset Analyses of 
Progression-Free Survival, OS and 
ORR
• included Subject follow-up section.
• included Follow-up Therapy section
• updated section 7.7 to include only 
Cohort 1
 
Version 2.1
26-Oct-2018
• CBR added to BOR analysis
• updated overall survival to include 
KM plot for responders Vs non-
responders.
• updated Baseline KPS score to remove 
< 80 and include 70 and < 70
• added additional population for BOR 
analysis
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Document 
Date of Issues 
Summary of Changes
Version 2.2
13-Dec-2018
• added additional population for BOR 
analysis
Version 2.3
21-Oct-2019
 
 
•
 
Version 2.3
08-Jan-2020
• Updated Efficacy section for including 
or removing the populations.
• Updated IP and F population 
definitions to consider Treated 
subjects rather than enrolled subjects.
 
 
Version 2.3
02-Feb-2020
 
Version 2.4
14Apr2020
• Revise section 1.0 (schedule of 
analyses) per client request (added 
‘treatment’ to end of first sentence.)
Version 2.4
15May2020
• Added Landmark Analysis for OS 
from 6 ,12 Months.
• Removed Not qualified IMAE listing 
description.
Version 2.4
23May2020
• Removed Lab SI units summary.
• Removed Clopper- Pearson CI from 
primary endpoint analysis.
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Document 
Date of Issues 
Summary of Changes
Version 2.4
26May2020
• Added phrase in section 7.1: 
“Analyses based on the combination 
of Cohorts 2-4 are considered not 
necessary for CSR as Cohort 4 has 
low KPS and tolerability may not be 
the same with other groups.”
• Added phrase in landmark analyses: 
“These Landmark Analyses will not 
display hazard ratios, CI, median and 
p values.”
• Added phrase in section 7.5.2.6:“
(population for this factor is All 
Treated Subjects with Intracranial 
Progression in Cohort 3)”
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7.3.1 
Subject Disposition.................................................................................................22
7.3.2 
Demographic and Baseline Characteristics............................................................22
7.3.3 
Medical History......................................................................................................23
7.3.4 
Prior Therapy Agents .............................................................................................23
7.3.5 
Baseline Examinations............................................................................................24
7.4 
Extent of Exposure.................................................................................................24
7.4.1 
Administration of Study Therapy.............................................................................24
7.4.2 
Modifications of Study Therapy..............................................................................26
7.4.2.1 
Dose Delays ...........................................................................................................26
7.4.2.2 
Dose Reductions/Escalations and Infusion Interruption..........................................26
7.5 
Efficacy..................................................................................................................27
7.5.1 
Secondary Analyses................................................................................................27
7.5.1.1 
Progression-Free Survival 1...................................................................................27
7.5.1.2 
Objective Response Rate and Clinical Benefit Rate.................................................27
7.5.1.3 
Time to Response....................................................................................................27
7.5.1.4 
Duration of Response.............................................................................................28
7.6 
Safety 
.....................................................................................................................30
7.6.1 
Primary Analyses....................................................................................................30
7.6.1.1 
Incidence of High Grade Immune-Mediated Adverse Events...................................30
7.6.2 
Secondary Analyses................................................................................................30
7.6.2.1 
Characterization of Outcome of High Grade Immune-Mediated Adverse 
Events.....................................................................................................................30
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7.6.4 
Laboratory Abnormalities.......................................................................................32
7.6.4.1 
Hematology 
............................................................................................................32
7.6.4.2 
Serum Chemistry ....................................................................................................32
7.6.4.3 
Electrolytes.............................................................................................................32
7.6.4.4 
Additional Analyses................................................................................................32
7.6.5 
Vital Signs and Pulse Oximetry...............................................................................32
7.6.7 
Pregnancy..............................................................................................................33
7.6.8 
Adverse Event By Subgroup....................................................................................33
7.8.1 
Distribution of PD-L1 Expression...........................................................................34
8 
CONVENTIONS....................................................................................................36
9 
CONTENT OF REPORTS ............................................ .........................................36
9.1 
Clinical Study Report.............................................................................................36
9.2 
Other Reports and Reviews.....................................................................................36
9.2.1 
Safety Reviews........................................................................................................36
APPENDIX 1 
INTERNATIONAL METASTATIC RCC DATABASE 
CONSORTIUM (IMDC) PROGNOSTIC CRITERIA............................38
APPENDIX 2 
CALCULATION OF TOTAL SCORE IN EQ-5D USING US 
TTO       CONVENTION .......................................................................39
APPENDIX 3 
ADVERSE EVENTS OF INTEREST DEFINITION AND 
CONVENTIONS....................................................................................40
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APPENDIX 1 INTERNATIONAL METASTATIC RCC DATABASE CONSORTIUM 
(IMDC) PROGNOSTIC CRITERIA
Adverse Prognostic Factors
Clinical
KPS < 80%
Time from diagnosis to treatment < 1 year
Laboratory
Hemoglobin < LLN
Corrected calcium > ULN
Absolute neutrophil count > ULN
Platelet count > ULN
LLN = Lower limit of normal
ULN = Upper limit of normal
Corrected calcium (mg/dL) = measured total Ca (mg/dL) + 0.8 (4.0 - serum albumin [g/dL]), where 4.0 represents 
the average albumin level in g/dL.
Corrected calcium (mmol/L) = measured total Ca (mmol/L) + 0.02 (40 - serum albumin [g/L]), where 40 represents 
the average albumin level in g/L
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APPENDIX 3 
ADVERSE EVENTS OF INTEREST DEFINITION AND 
CONVENTIONS
The  adverse  events  of  interest  
including  IMAE,  select  AE,  and  other  event  of  special  interest 
consist  of  a  list  of  preferred  terms  grouped by  specific  category  and  by  subcategory. These 
categories and subcategories are defined by the Sponsor and the list that is most current at the time 
of analysis will be used. Also, changes may be made to this list with each new version of MedDRA.
Time-to onset definition
Time-to onset of AE (any grade) for a specific category (e.g. pulmonary events, gastrointestinal 
events, ...) is defined as the time between the day of the first dose of study treatment and the onset 
date of the earliest AE (of any grade) in this category.
If  
the  subject  did  not  experience  an AE  (of  any  grade)  
in  
the  category,  
time-to  onset  will  be 
censored at the maximum follow-up time of all subjects in their respective treatment group (i.e for 
subjects without an event, follow-up time is defined from first dosing date up to last dosing date 
+30 days (or 100 days depending on the analysis) if subjects are off treatment and followed for at 
least  30 days (or 100 days depending on the analysis) , otherwise it is defined up to the last known 
alive date). The resulting Kaplan-Meier plot will  
represent the  cumulative  
rate of the select AE 
(any grade) in the category over time.
Time-to onset of AE (grade 3-5) for a specific category is defined similarly but restricted to grade 
3-5 AEs.
Time-to  onset  of  drug-related  (grade  3-5  or  any  grade)  AE  for  a  specific  category  is  defined 
similarly but restricted to drug-related AEs.
Time-to  onset  for  a  specific  subcategory  is  defined  similarly  but  restricted  to  event  of  this 
subcategory.
Time-to resolution definition
In order to derive the time-to resolution, overlapping or contiguous AEs within a specific category 
will be collapsed into what will be termed “clustered” AEs. For example, if a subject (without pre-
treatment AE) experienced an AE from 1st to 5th January, another AE (with different PT but within 
same category) from 6th to 11th January and same AE from 10th to 12th January, these will be 
collapsed into one clustered AE from 1st to 12th January. Table A3-1summarizes key derivation 
steps for each type of clustered AEs.
Time-to resolution of AE (any grade) for a specific category is defined as the longest time from 
onset to complete resolution or improvement to the grade at baseline among all clustered select 
AEs in this category experienced by the subject. Events which worsened into grade 5 events (death) 
or have a resolution date equal to the date of death are considered unresolved. If a clustered AE is 
considered  as  unresolved,  the  resolution  date  will  be  censored to  the  last  known  date  alive. 
Improvement  
to  
the  grade at  baseline  
implies  
that all  different  adverse events  
in  
the  clustered 
adverse event should at least have improved to the corresponding (i.e. with same preferred term) 
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