Clinical trial NCT02599402
Conditions: Melanoma
Sponsor: Bristol-Myers Squibb
Start date: 2015-12-20; Completion date: 2020-02-10
Enrollment: 533 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the effects of combination treatment of Nivolumab with Ipilimumab followed by Nivolumab monotherapy in patients with previously untreated advanced Melanoma.

Detailed description:

Arms: arm 1: Nivolumab + Ipilimumab specified dose on specified days arm 2: Nivolumab specified dose on specified days
Interventions: intervention 1: Nivolumab intervention 2: Ipilimumab
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 


Clinical Protocol
CA209401
BMS-936558
nivolumab
Revised Protocol No.: 06
Date: 31-Jul-2018
2
be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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Revised Protocol No.: 06
Date: 31-Jul-2018
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 06
31-Jul-2018
•
Follow-up Phase shortened from 5 years after first dose to 
2 years after first dose (or 2 years of treatment + 100 days 
of FU)
•
For patients discontinued in Part I, follow-up visits will be 
onsite only
•
Contraception wording changed based on updated 
Investigator’s Brochure for nivolumab
•
Changes made to align with nivolumab program standards
Revised Protocol 05
19-Aug-2016
Incorporates Amendment 06
Amendment 06
19-Aug-2016
Incorporates the updated Pulmonary, Renal, and Skin Adverse 
Event Management Algorithms that were mistakenly not 
included in the Revised Protocol associated with Amendment 
05.
Revised Protocol 04
03-Aug-2016
Incorporated Amendment 05 and Administrative Letter 02
Amendment 05
03-Aug-2016
•
To revise the Management Algorithms to align with the 
new recommendations
•
To align with the nivolumab program standards, including 
changes to the duration of contraception use
•
To address minor inconsistencies in the protocol
•
To clarify that tumor assessments beyond Week 12 should 
be made according to the investigator’s assessment. 
Administrative Letter 02
28-Jun-2016
•
Update the address of the Bristol-Myers Squibb Research 
and Development facility where the Medical Monitor is 
located
•
Clarify that the lettered numbering of the Inclusion Criteria 
was inadvertently re-numbered during the creation of the 
revised protocol associated with Amendment 04
•
Clarify the Dose Delay Criteria for Grade 2 drug-related 
creatinine, aspartate aminotransferase, alanine 
aminotransferase, or total bilirubin
•
Clarify that tumor scans should also be completed for 
subjects who discontinue during the nivolumab and 
ipilimumab combination part (Part I) of the trial. 
Revised Protocol 03
25-May-2016
Incorporated Amendment 04 and Administrative Letter 01
Amendment 04
25-May-2016
•
Changes the nivolumab monotherapy dose in Part II to 240 
mg flat dose for those subjects who enroll after the 
implementation of Amendment 04
•
Decreases the infusion times of nivolumab and ipilimumab
Administrative Letter 01
22-Mar-2016
•
Align chemistry laboratory procedures throughout the 
screening, treatment, and follow-up phases and to remove 
the term serum from these procedures. 
•
Align timing of receipt of testing results and dosing 
between the Time and Events Schedules and Section 5.3, 
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Revised Protocol No.: 06
Date: 31-Jul-2018
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Document
Date of Issue
Summary of Change
Safety Assessments. 
•
Add footnotes to Table 5.1-2, On Study Assessments Part I: 
Cycles 1 through 4 (Nivolumab Plus Ipilimumab) and 
Table 5.1-3, On-Treatment Assessments Part II: Cycles 5 
and Beyond (Nivolumab Monotherapy) to clarify that 
procedures for each time point should also be delayed if the 
dose is delayed
•
Clarify that investigators should follow the Management 
Algorithms in Appendix 1 for all grade adverse events 
rather than only Grades 3-4 in the Notes sections of Tables 
5.1-2, On-Study Assessments Part I: Cycles 1 through 4 
(Nivolumab Plus Ipilimumab) and 5.1-3, On-Treatment 
Assessments Part II: Cycles 5 and Beyond (Nivolumab 
Monotherapy).
•
Remove dosing windows Tables 5.1-2, On-Study 
Assessments Part I: Cycles 1 through 4 (Nivolumab Plus 
Ipilimumab) and 5.1-3, On-Treatment Assessments Part II: 
Cycles 5 and Beyond (Nivolumab Monotherapy).
•
Add windows to Table 5.1-4, Follow Up Assessments for 
Subjects who Discontinue in Part I
•
Align the footnotes and Notes section related collection of 
adverse events in Tables 5.1-4, Follow Up Assessments for 
Subjects who Discontinue in Part I and 5.1-5, Follow-Up 
Assessments for Subjects who Discontinue in Part II to 
each other for consistency. 
•
Remove the “Every 4 Week Column” from Table 5.1-5, 
Follow-Up Assessments for Subjects who Discontinue in 
Part II
•
Provide clarity on the timing of dosing when lipase test 
results are not available prior to dosing in Section 5.3, 
Safety Assessments. 
•
Provide clarity on the timing of dosing in relation to receipt 
of test results as it differs for baseline assessments and on-
treatment assessments. 
Revised Protocol 02
05-Feb-2016
Incorporated Amendment 02
Amendment 02
05-Feb-2016
Removed Human Immunodeficiency Virus (HIV) or Acquired 
Immunodeficiency Syndrome Exclusion Criterion
Revised Protocol 01
06-Jan-2016
Incorporated Amendment 01
Amendment 01
06-Jan-2016
•
Changes Exclusion Criteria to known history of Human 
Immunodeficiency Virus (HIV) or Acquired 
Immunodeficiency Syndrome and removes HIV testing 
from the screening procedures.
•
Adds the definition of a Suspected Unexpected Serious 
Adverse Event
•
Requires local regulatory approval if applicable prior 
implementation of deviations or changes to the protocol.
Original Protocol
03-Jun-2015
Not applicable
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SYNOPSIS
Clinical Protocol CA209401 
Protocol Title: Clinical Trial of Nivolumab (BMS-936558) Combined with Ipilimumab Followed by Nivolumab 
Monotherapy as First-Line Therapy of Subjects with Histologically Confirmed Stage III (Unresectable) or Stage IV 
Melanoma
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Nivolumab 1 mg/kg IV over 30 minutes in combination with ipilimumab 3 mg/kg IV over 30 minutes 
every 3 weeks for 4 doses followed by nivolumab 3 mg/kg IV over 30 minutes every 2 weeks for up to 24 months 
from the first dose of regimen therapy. After implementation of Amendment 04, subjects will receive nivolumab 
240 mg IV as a 30-minute infusion every 2 weeks in Part II.
Study Phase: 3b
Research Hypothesis: To characterize the incidence of high-grade (CTCAE v4.0 Grade 3 or higher), 
treatment-related, select adverse events of potentially immune-mediated etiology observed in a patient population 
reflective of routine, clinical practice and receiving nivolumab plus ipilimumab combination therapy in the first-line 
setting of advanced melanoma.
Objectives: The primary objective of this study is to determine the incidence of high-grade (CTCAE v4.0 
Grades 3-5), treatment-related, select adverse events of potentially immune-mediated etiology (pulmonary, 
gastrointestinal, skin, renal, hepatic, endocrine, infusion-related, or hypersensitivity) of nivolumab plus ipilimumab 
combination regimen as first-line therapy for unresectable or metastatic melanoma.
The secondary objectives of this study are:
•
To determine the incidence and to characterize the outcome (duration of serious adverse events [SAE]
treatment, dose of immune-modulating agents [ie, steroids] used, time to event onset, and event resolution, and 
worst grade of event) of high-grade (CTCAE v4.0 Grade 3 or higher), select adverse events of potentially 
immune-mediated etiology in subjects with unresectable or metastatic melanoma treated with nivolumab and 
ipilimumab combination regimen 
•
To estimate overall survival (OS) in all treated subjects 
•
To assess safety, tolerability, investigator-assessed objective response rate (ORR), progression-free survival 
(PFS), and OS in all subjects and in a subset of with Eastern Cooperative Oncology Group (ECOG) 
Performance Status (PS) 0-1, ECOG PS 2, ocular and mucosal melanoma, and brain metastasis
Study Design: The study will include subjects who will receive first-line therapy for advanced disease with 
histologically-confirmed unresectable stage III or stage IV melanoma, ages 18 or older. Subjects will be treated with 
nivolumab 1 mg/kg IV as a 30-minute infusion combined with ipilimumab 3 mg/kg IV as a 30-minute infusion 
every 3 weeks for 4 doses (Part I) and then nivolumab 3 mg/kg IV every 2 weeks (Part II) until progression, 
unacceptable toxicity, or a maximum of 24 months from first combination dose (Part I and Part II), whichever 
comes first. At sites who begin enrolling subjects after the implementation of Amendment 04, subjects will receive 
nivolumab 240 mg IV as a 30-minute infusion every 2 weeks in Part II. Approximately 768 subjects will be 
considered for enrollment, and approximately 615 will be treated.
This study will consist of 3 phases: Screening, Treatment, and Follow-up. 
The Screening Phase begins by establishing the subject’s initial eligibility and signing of the informed consent form 
(ICF). Subjects are enrolled using the Interactive Voice Response System (IVRS).
 
 
 
 
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The Treatment Phase begins with the vial assignment call to the IVRS. A negative pregnancy test should be 
documented within 24 hours prior to the start of investigational product. An extension of up to 72 hours prior to the 
first dose of nivolumab and ipilimumab is allowed in situations where results cannot be obtained within the standard 
24 hour window.
For Part I, nivolumab and ipilimumab are administered every 3 weeks for 4 doses. For Part II, nivolumab 
monotherapy is administered every 2 weeks for up to 24 months from the first combination dose (Part I and II). 
Subjects may be treated for more than 24 months for a maximum of 50 cycles in case an on-hold period occurs 
during the Treatment Phase. 
An initial tumor assessment is to be completed at Week 12 (±5 days) after the first treatment dose. Further tumor 
assessments are recommended to be completed as required by local standards of care or at the investigator’s 
discretion and are recommended every 8 weeks until documented tumor progression. 
The Follow-up Phase begins when the decision to discontinue a subject from study therapy is made (no further 
treatment with study therapy):
•
Subjects who discontinue therapy in Part I are recommended to be followed by direct contact (office visit) 
every 4 weeks for up to 100 days after the last dose of regimen therapy. After completion of the onsite 
follow-up visits (for up to 100 days), subjects will be followed every 24 weeks ± 2 weeks for survival 
either by direct visit or via telephone contact. OS will be followed from the start of therapy up to 2 years or 
until death, withdrawal of study consent, or lost-to-follow-up, whichever comes first.
•
For subjects who complete or discontinue therapy in Part II, subjects will have 2 follow-up visits (office 
visits): one approximately 30 days after the last dose of study drug and one approximately 100 days after 
the last dose of study drug. After completion of the first 2 follow-up visits, subjects will be followed every 
24 weeks ± 2 weeks for survival either by direct contact or via telephone contact. OS will be followed 
from the start of therapy up to 2 years (+ 100 days following the last dose of study treatment), or until 
death, withdrawal of study consent, or lost-to-follow-up, whichever comes first.
•
For subjects who complete therapy in Part II (2 years of treatment), subjects will have 2 follow-up visits 
(office visits): one approximately 30 days after the last dose of study drug and one approximately 100 days 
after the last dose of study drug. 
Subjects who discontinue treatment for reasons other than tumor progression will continue to have tumor 
assessments according to the local standard of care for up to 2 years. All adverse events (adverse events) will be 
documented for a minimum of 100 days after last dose.
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Study Population:
Key Inclusion Criteria:
a)
Subjects with histologically-confirmed unresectable stage III or stage IV melanoma as per AJCC 2010 
staging system, including mucosal and ocular melanoma, regardless of BRAF mutation status
b)
Subjects are included if they are newly diagnosed with advanced/metastatic disease and have not received 
prior systemic treatment for their advanced disease. 
NOTE: Prior adjuvant or neoadjuvant melanoma therapy (including anti-CTLA-4, anti-PD-1, anti-PD-L1, 
anti-PD-L2, or any other antibody or drug specifically targeting T-cell costimulation or checkpoint 
pathways, such as anti-CD-137) is permitted if the therapy was used in the adjuvant or neoadjuvant setting 
but not in the metastatic setting. These drugs must be discontinued 6 months prior to study entry. All AEs 
related to prior adjuvant or neoadjuvant therapy must have either returned to baseline, and eligible patients 
must not have experienced severe or life-threatening irAEs except those that are unlikely to reoccur with 
standard countermeasures (eg, hormone replacement after adrenal crisis).
c)
Subjects with brain metastases are eligible if these have been treated and there is no magnetic resonance 
imaging (MRI) evidence of progression for at least 2 weeks after treatment is complete and within 6 weeks 
prior to first dose of study drug administration. (If MRI is contraindicated, CT scan is acceptable). There 
must also be no requirement for high doses of systemic corticosteroids that could result in 
immunosuppression (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug 
administration.
i)
Subjects are eligible if they have previously untreated brain metastases and are neurologically 
asymptomatic (This criterion is restricted to the investigators who have treated at least 3 patients with 
nivolumab plus ipilimumab combination regimen):
(1) No clinical requirement for local intervention (surgery, radiosurgery, corticosteroid therapy) or 
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other systemic therapy.
(2) Subjects must be free of neurologic signs and symptoms related to metastatic brain lesions and 
must not have received systemic corticosteroid therapy in the 14 days prior to beginning protocol 
therapy.
ii)
If patients had been previously treated and then developed asymptomatic progression (This criterion 
with details below is restricted to the investigators who have treated at least 3 patients with nivolumab 
plus ipilimumab combination regimen)
(1) Prior stereotactic radiotherapy (SRT) and prior excision of up to 3 melanoma brain metastases is 
permitted if there has been complete recovery, with no neurologic sequelae.
(2) Growth or change in a lesion previously irradiated will not be considered measurable. Regrowth in 
cavity of previously excised lesion will not be considered measurable. 
(3) Any prior surgery or radiotherapy must have occurred at least 6 weeks before the start of dosing 
for this study.
d)
ECOG PS 0-1
e)
ECOG PS of 2 (This criterion is restricted to investigators who have treated at least 3 patients with 
nivolumab plus ipilimumab combination regimen)
f)
Tissue tumor (archival or recent acquisition) must be available (block or a minimum of 10 unstained slides 
of FFPE tissue) for correlative studies
Key Exclusion Criteria
a)
Leptomenigeal metastases
b)
As of Amendment 04, this criterion is no longer applicable
c)
Subjects previously treated with SRT > 3 lesions in the brain
d)
Brain lesion > 3 cm
e)
History of carcinomatous meningitis (lumbar puncture is not required)
f)
Subjects with active, known, or suspected autoimmune disease. Subjects with Type I diabetes mellitus, 
hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) 
not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger 
are permitted to enroll. 
g)
Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone 
equivalent) or other immunosuppressive medications within 14 days of study drug administration. Inhaled 
or topical steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted 
in the absence of active autoimmune disease. 
h)
All toxicities attributed to prior anti-cancer therapy other than alopecia, fatigue, or peripheral neuropathy 
must have resolved to Grade 1 (NCI CTCAE version 4) or baseline before administration of study drug.
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational 
[Medicinal] Products (Non-IP/Non-IMP) as listed:
Study Drug for BMS-936558
Medication 
Potency 
IP/Non-IP 
Nivolumab
100 mg (10 mg/mL)
Or
40 mg (10 mg/mL)
IP
Ipilimumab
200 mg (5 mg/mL)
IP
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Study Assessments: The following safety assessments should be monitored every cycle, except where noted, 
starting with dosing until approximately 100 days following the discontinuation from study therapy, providing AEs 
have resolved:
•
AEs continuously throughout the study
•
Physical examination and physical measurements including weight and ECOG performance status
•
Complete blood counts (CBCs) with differential, including WBC, lymphocyte count, ANC, hemoglobin, 
hematocrit, and platelet count. Laboratory tests should be completed and reviewed within 72 hours prior to 
dosing.
•
Chemistry tests (BUN or serum urea level, creatinine, sodium, potassium, calcium, phosphate, chloride, 
magnesium, glucose, amylase, lipase, and LDH). Laboratory tests should be completed with 72 hours and 
reviewed prior to dosing. If sites are unable to obtain lipase results prior to dosing, dosing may still occur 
provided all other safety laboratory results including amylase are available and reviewed by the investigator 
prior to dosing.
•
Liver function tests including AST, ALT, total bilirubin, alkaline phosphatase, albumin. Laboratory tests 
should be completed within 72 hours and reviewed prior to dosing.
•
Thyroid function testing, including TSH (reflex to free T3 and free T4 if abnormal results), to be checked 
every 6 weeks. Laboratory tests should be completed within 72 hours and reviewed prior to dosing. 
•
Concomitant medications will be collected at the screening visit, throughout the Treatment Phase, and Follow-
up Phase. 
Subjects will also receive a weekly phone call to report AEs on the weeks without required study visits. After 
completion of the visits up to 100 days after the last dose of study drug, OS will be followed by direct contact (office 
visits) or via telephone contact, until death, withdrawal of study consent, or lost to follow-up for up to 2 years from 
the first dose of study treatment (+ 100 days following the last dose of study treatment). OS is defined as the time 
between the start of treatment and the date of death due to any cause.
Efficacy assessments include an initial tumor assessment at Week 12 (± 5 days) after first combination dose. Further 
tumor assessments to be completed as required by local standards of care or at the investigator’s discretion and are 
recommended every 8 weeks. Quality-of-life data will be measured using the EORTC QLQ-C30 every 2 cycles 
(6 weeks) during ipilimumab and nivolumab combination regimen treatment and then every 4 cycles (8 weeks) 
while receiving nivolumab monotherapy starting with Cycle 5.
Statistical Considerations:
Sample Size: Of 768 subjects who will be screened to receive first-line therapy for advanced disease with 
histologically confirmed stage III (unresectable) or stage IV melanoma, approximately 615 subjects will be treated 
with nivolumab and ipilimumab regimen. This sample size is based on the primary objective of the study: 
determining the incidence of high-grade (CTCAE v4.0 Grades 3-5), treatment-related, select adverse events of 
potentially immune-mediated etiology in subjects receiving first-line therapy for advanced disease. The sample size 
will allow for estimating an incidence of about 50% with a 95% confidence interval (CI) of (46.06%, 54.11%) under 
308 subjects with events among 615 treated subjects.
Endpoints:
The primary endpoint is the incidence of high-grade (CTCAE v4.0 Grade 3-5), 
treatment-related, select adverse events of potentially immune-mediated etiology (pulmonary, gastrointestinal, skin, 
renal, hepatic, endocrine, infusion-related, or hypersensitivity).
The secondary endpoints are:
•
Incidence of all high-grade (Grades 3-5), select adverse events 
•
Median time to onset and median time to resolution (Grades 3-4) of select adverse events
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•
Resolution of an AE is a subject experiencing complete resolution or improvement to the baseline grade for the 
AE
•
OS is defined as the time from first dosing date to the date of death. A subject who has not died will be 
censored at last known date alive. 
•
Safety and tolerability will be measured by the incidence of all AEs, treatment-related AEs, serious AEs, 
deaths, laboratory abnormalities, and select AEs such as pulmonary, gastrointestinal, skin, renal, hepatic, 
endocrine, infusion-related, or hypersensitivity. 
•
The ORR is defined as the number of subjects with a best overall response (BOR) of a complete response (CR) 
or partial response (PR) divided by the number of all treated subjects. BOR is defined as the best response 
designation, recorded between the date of first dose and the date of the initial objectively documented tumor 
progression by the investigator or the date of subsequent therapy, whichever occurs first. For subjects without 
documented progression or subsequent therapy, all available response designations will contribute to the BOR 
determination.
•
Investigator-assessed PFS is defined as radiological evidence of progression, significant clinical symptomatic 
progression, or the need to introduce a non-study drug therapy.
Analyses: Descriptive statistics will be presented for each of the endpoints. The analysis of primary, 
secondary, and exploratory endpoints will be reported for the full safety analysis set (all treated subjects) and by 
subgroups based on ECOG PS, brain metastasis, ocular and mucosal melanoma, and investigator experience in 
treating with the nivolumab plus ipilimumab combination regimen. The number and percentage of subjects who 
report high-grade (Grade 3-5), treatment-related, select adverse events of potentially immune-mediated etiology will 
be summarized for all treated subjects overall. High-grade (Grade 3-5), treatment-related select adverse events will 
be tabulated using worst grade per CTCAE v4.0 criteria by system organ class and Medical Dictionary for 
Regulatory Affairs (MedDRA) preferred term. The number and percentage of subjects who report high-grade (Grade 
3-5), treatment-related, select adverse events of potentially immune-mediated etiology will be summarized for all 
treated subjects overall and by subgroup. High-grade (Grade 3-5), treatment-related, select adverse events will be 
tabulated using worst grade per CTCAE v4.0 criteria by system organ class and Medical Dictionary for Regulatory 
Affairs (MedDRA) preferred term. Time to onset and resolution of the events, dose of immune modulating 
medications subjects received for the events, and the event by grade will also be tabulated for all treated subjects and 
by subgroups. Cumulative doses of immune-modulating agents will be summarized and reported.
Time to onset and resolution of the events, dose of immune modulating medications subjects received for the events, 
and the event by grade will also be tabulated for all treated subjects and by subgroup. All safety data will be listed 
and tabulated for all treated subjects. All AEs, treatment-related AEs, serious AEs, deaths, and select AEs such as 
pulmonary, gastrointestinal, skin, renal, hepatic, endocrine, infusion-related, or hypersensitivity will be summarized 
by system organ class and preferred term, and coded according to the most current version of MedDRA.
OS will be summarized by Kaplan-Meier method for all treated subjects and by cohort. Median values of OS, along 
with 2-sided 95% CI using Brookmeyer and Crowley method, will be calculated. 
The investigator-assessed ORR will be summarized by binomial response rates and their corresponding 2-sided 95% 
exact CIs using the Clopper-Pearson method. This analysis will be performed for all response evaluable subjects and 
by subgroup. The DOR will be summarized for subjects who achieve confirmed PR or CR using the Kaplan-Meier 
method. Median values of DOR, along with 2-sided 95% CI using Brookmeyer and Crowley method, will also be 
calculated. The abovementioned OS, investigator-assessed ORR, and safety and tolerability will be conducted 
specifically for subjects with PS 2, ocular or mucosal melanoma.
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2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials (eg, 
advertisements), and any other written information to be provided to subjects. The investigator or 
BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives 
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood. 
Allow time necessary for subject or subject's legally acceptable representative to inquire about 
the details of the study.
Obtain an informed consent signed and personally dated by the subject or the subject's legally 
acceptable representative and by the person who conducted the informed consent discussion. 
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 subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the subject.
Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the subject's 
willingness to continue participation in the study. This communication should be documented. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF 
and, in the US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The subject 
must also be informed about the nature of the study to the extent compatible with his or her 
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understanding, and should this subject become capable, he or she should personally sign and date 
the consent form as soon as possible. The explicit wish of a subject who is unable to give his or 
her written consent, but who is capable of forming an opinion and assessing information to 
refuse participation in, or to be withdrawn from, the clinical study at any time should be 
considered by the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
The study will include subjects who will receive first-line therapy for advanced disease with 
histologically-confirmed unresectable stage III or stage IV melanoma, ages 18 or older. Subjects 
will be treated with nivolumab 1 mg/kg IV as a 30-minute infusion combined with ipilimumab 
3 mg/kg IV as a 30-minute infusion every 3 weeks for 4 doses (Part I) and then nivolumab 3 
mg/kg IV every 2 weeks (Part II) until progression, unacceptable toxicity, or a maximum of 24 
months from the first combination dose (Part I and Part II), whichever comes first. Subjects may 
be treated for more than 24 months for a maximum of 50 cycles in case an on-hold period occurs 
during the Treatment Phase. At sites who begin enrolling subjects after the implementation of 
Amendment 04, subjects will receive nivolumab 240 mg IV as a 30-minute infusion every 2 
weeks in Part II. Approximately 768 subjects will be considered for enrollment, and 
approximately 615 will be treated.
This study will assess the safety and efficacy of nivolumab combined with ipilimumab in adults 
(≥ 18 years) with stage III (unresectable) or stage IV melanoma, as per the American Joint 
Committee on Cancer (AJCC) staging system. Subjects must not have received prior therapy for 
the treatment for metastatic disease.
This study will consist of 3 phases: Screening, Treatment, and Follow-up. 
The Screening Phase begins by establishing the subject’s initial eligibility and signing of the 
informed consent form (ICF). Subjects are enrolled using the Interactive Voice Response System 
(IVRS) (Table 5.1-1).
Per Amendment 04 (25-May-2016): Tumor tissue (archival or recent acquisition) must be 
available for assessment of tumor PD-L1 expression by immunohistochemical and other tumor 
tissue biomarker studies. Subjects must consent to allow the acquisition of formalin-fixed 
paraffin-embedded (FFPE) material (block or 10 unstained slides) by study personnel for 
performance of correlative tissue studies. 
The Treatment Phase begins with the vial assignment call to the IVRS. A negative pregnancy test 
should be documented within 24 hours prior to the start of investigational product. An extension 
of up to 72 hours prior to the first dose of nivolumab and ipilimumab is allowed in situations 
where pregnancy test results cannot be obtained within the standard 24 hour window.
For Part I, nivolumab and ipilimumab are administered every 3 weeks for 4 doses (Table 5.1-2). 
If subjects discontinue therapy during Part I, nivolumab monotherapy can be continued as 
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described in Section 4.5.5. For Part II, nivolumab monotherapy is administered every 2 weeks 
(Table 5.1-3) until 24 months after the first combination dose (Part I and II). Subjects may be 
treated for more than 24 months for a maximum of 50 cycles in case an on-hold period occurs 
during the Treatment Phase.
Windows for dosing of both Part I and Part II are discussed in Section 4.5.
An initial tumor assessment is to be completed at Week 12 (± 5 days) after the first treatment 
dose. Further tumor assessments are recommended to be completed as required by local 
standards of care or at the investigator’s discretion and are recommended every 8 weeks until 
documented tumor progression. 
Subjects treated with the study drugs will be permitted to continue treatment beyond initial PD as 
assessed by the investigator’s clinical judgment and local standards of care as long as they meet 
the criteria specified in Section 4.5.8. 
The Treatment Phase ends when the subject is discontinued from study therapy. For a complete 
list of reasons for treatment discontinuation, see Sections 3.5 and 4.5.6.
The Follow-up Phase begins when the decision to discontinue a subject from study therapy is 
made (no further treatment with study therapy) (Table 5.1-4 and Table 5.1-5):
•
Subjects who discontinue therapy in Part I are recommended to be followed by direct 
contact (office visit) every 4 weeks for up to 100 days after the last dose of combination 
regimen therapy. After completion of the onsite follow-up visits (for up to 100 days), 
subjects will be followed every 24 weeks ± 2 weeks for survival either by direct visit or via 
telephone contact. OS will be followed from the start of therapy up to 2 years or until death, 
withdrawal of study consent, or lost-to-follow-up, whichever comes first.
•
For subjects who complete or discontinue therapy in Part II, subjects will have 2 follow-up 
visits (office visits): one approximately 30 days after the last dose of study drug and one 
approximately 100 days after the last dose of study drug. After completion of the first 2 
follow-up visits, subjects will be followed every 24 weeks ± 2 weeks for survival either by 
phone contact or direct contact. OS will be followed in accordance with Table 5.1-4 and 
Table 5.1-5 from the start of therapy up to 2 years (+ 100 days following the last dose of 
study treatment), or until death, withdrawal of study consent, or lost-to-follow-up, 
whichever comes first. 
•
For subjects who complete therapy in Part II (2 years of treatment), subjects will have 2 
follow-up visits (office visits): one approximately 30 days after the last dose of study drug 
and one approximately 100 days after the last dose of study drug. 
Subjects who discontinue treatment for reasons other than tumor progression will continue to 
have tumor assessments according to the local standards of care and in accordance with Table 
5.1-4 and Table 5.1-5. 
Subjects will be followed for drug-related toxicities until these toxicities resolve, return to 
baseline, are deemed irreversible, lost to follow up, or withdrawal of study consent. All AEs will 
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be documented for a minimum of 100 days after last dose. Additional details regarding the 
follow up are discussed in Section 5.3, Table 5.1-4, and Table 5.1-5. 
The study design schematic is presented in Figure 3.1-1.
Figure 3.1-1:
Study Design Schematic
The start of the trial is defined as the first patient’s first study visit. End of trial is defined as the 
last patient’s last study visit. Study completion is defined as the final date on which data for the 
primary endpoint was or is expected to be collected, if this is not the same.
Enrollment of new subjects into the study will stop at the time of marketing authorization 
approval. In certain countries where nivolumab plus ipilimumab combination regimen may not 
be immediately available upon marketing authorization and subject to country specific 
amendments, enrollment may remain open for a maximum of 1 year after marketing 
authorization is granted. 
3.2
Post Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study drug for the maximum treatment duration specified in 
Section 3.1. Study drug will be provided via an extension of the study, a rollover study requiring 
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approval by responsible health authority and ethics committee or through another mechanism at 
the discretion of BMS. 
BMS reserves the right to terminate access to BMS supplied study drug if any of the following 
occur: a) the marketing application is rejected by responsible health authority; b) the study is 
terminated due to safety concerns; c) the subject can obtain medication from a government 
sponsored or private health program; or d) therapeutic alternatives become available in the local 
market.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC-approved written informed consent 
form in accordance with regulatory and local guidelines. This must be obtained before the 
performance of any protocol-related procedures that are not part of normal subject care.
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
and laboratory tests, including completion of quality of life questionnaires and other 
requirements of the study. 
2. Target Population
a) Subjects with histologically-confirmed unresectable stage III or stage IV melanoma as 
per AJCC 2010 staging system, including mucosal and ocular melanoma, regardless of 
BRAF mutation status. 73
b) Subjects are included if they are newly diagnosed with advanced/metastatic disease and 
have not received prior systemic treatment for their advanced disease. 
NOTE: Prior adjuvant or neoadjuvant melanoma therapy (including anti-CTLA-4, 
anti-PD-1, anti-PD-L1, anti-PD-L2, or any other antibody or drug specifically targeting 
T-cell costimulation or checkpoint pathways, such as anti-CD-137) is permitted if the 
therapy was used in the adjuvant or neoadjuvant setting but not in the metastatic setting. 
These drugs must be discontinued 6 months prior to study entry. All AEs related to prior 
adjuvant or neoadjuvant therapy must have returned to baseline, and eligible patients 
must not have experienced severe or life-threatening irAEs except those that are unlikely 
to reoccur with standard countermeasures (eg, hormone replacement after adrenal crisis).
c) Although lesions measured by physical exam (calipers) can be considered measurable, at 
least 1 target lesion must be measurable by CT or MRI per RECIST 1.174
d) Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to the 
first dose of study drug
e) Subjects with brain metastases are eligible if these metastases have been treated and there 
is no magnetic resonance imaging (MRI) evidence of progression for at least 2 weeks 
after treatment is complete and within 6 weeks prior to first dose of study drug 
administration. (If MRI is contraindicated, CT scan is acceptable.) There must also be no 
requirement for high doses of systemic corticosteroids that could result in 
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immunosuppression (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to 
study drug administration.
i.
Subjects are eligible if they have previously untreated brain metastases and are 
neurologically asymptomatic (This criterion is restricted to investigators who have 
treated at least 3 patients with nivolumab plus ipilimumab combination regimen)
1) No clinical requirement for local intervention (surgery, radiosurgery, 
corticosteroid therapy) or other systemic therapy.
2) Subjects must be free of neurologic signs and symptoms related to metastatic 
brain lesions and must not have received systemic corticosteroid therapy in 
the 14 days prior to beginning protocol therapy.
ii.
If subjects had been previously treated, and then developed asymptomatic progression
(This criterion with details below is restricted to investigators who have treated at 
least 3 patients with nivolumab plus ipilimumab combination regimen)
1) Prior stereotactic radiotherapy (SRT) and prior excision of up to 3 melanoma 
brain metastases is permitted if there has been complete recovery, with no 
neurologic sequelae.
2) Growth or change in a lesion previously irradiated will not be considered 
measurable. Regrowth in cavity of previously excised lesion will not be 
considered measurable. 
3) Any prior surgery or radiotherapy must have occurred at least 6 weeks before 
the start of dosing for this study
f)
Screening laboratory values must meet the following criteria and should be obtained prior
to commencement of treatment:
i.
White blood counts (WBC) ≥2000/μL
ii.
Neutrophils ≥1500/μL
iii.
Platelets ≥100 X 10³/μL
iv.
Hemoglobin ≥9.0 g/dL
v.
Creatinine serum creatinine ≤1.5 × upper limit of normal [ULN] or creatinine 
clearance (CrCL) > 40 mL/minute (using Cockcroft/Gault formula)
i)
Female CrCl= [(140- age in years) × weight in kg X 0.85) ÷ (72 × serum 
creatinine in mg/dL)]
ii) Male CrCl= [(140- age in years) × weight in kg × 1.00) ÷ (72 × serum creatinine 
in mg/dL)]
vi.
AST ≤3 × ULN
vii.
ALT ≤ 3 × ULN
viii.
Total bilirubin ≤1.5 × ULN (except subjects with Gilbert Syndrome who can have 
total bilirubin < 3.0 mg/dL)
g) Subject Re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, has not been treated). If re-enrolled, 
the subject must be re-consented.
h) ECOG PS 0-1
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i)
ECOG PS of 2 (This criterion is restricted to investigators who have treated at least 
3 patients with nivolumab plus ipilimumab combination regimen)
j)
Tissue tumor (archival or recent acquisition) must be available (block or a minimum of 
10 unstained slides of FFPE tissue) for correlative studies
3. Age and Reproductive Status
a) Men and women, aged ≥18 years
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 
hours prior to the start of study drug
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with study drugs plus 5 half-lives plus 30 days (duration of ovulatory cycle). 
Because the half-life of nivolumab is longer than that of ipilimumab, subjects must agree 
to continue contraception for a total of 5 months post-treatment completion.
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with nivolumab plus 5 half-lives 
of the study drug plus 90 days (duration of sperm turnover). Because the half-life of 
nivolumab is longer than that of ipilimumab, subjects must agree to continue 
contraception for a total of 7 months post-treatment completion.
f)
Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However, they must still undergo pregnancy 
testing as described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% when used consistently and correctly. Local laws and regulations may 
require use of alternative and/or additional contraception methods.
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.
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
•
Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
implantable, or injectable)
•
Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants, and 
intrauterine hormone-releasing system (IUS)
•
Bilateral tubal occlusion 
•
Vasectomized partner
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NOTE: 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.
•
Intrauterine devices (IUDs)
•
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 5.
−
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence.
UNACCEPTABLE METHODS OF CONTRACEPTION
•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal sponge with spermicide
•
Male or female condom with or without spermicide. Male and female condoms must not be 
used simultaneously.
•
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.
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•
Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end 
of treatment in the male participant.
•
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile vaginal intercourse or use a male condom during each episode of penile 
penetration during the treatment and until 7 months after the end of study treatment. 
•
Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment.
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Leptomeningeal metastases 
b) Subjects previously treated with SRT > 3 lesions in the brain
c) Brain lesion > 3 cm
d) History of carcinomatous meningitis (lumbar puncture not required)
2. Medical History and Concurrent Diseases
a) As of Amendment 04, this criterion is not applicable
b) Subjects who are expected to require any form of systemic antineoplastic therapy while 
receiving study drug(s)
c) Subjects with active, known, or suspected autoimmune disease. Subjects with Type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions 
not expected to recur in the absence of an external trigger are permitted to enroll. 
d) Subjects with previous malignancies (except non-melanoma skin cancer and the 
following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, or 
breast) are excluded unless a complete remission was achieved at least 1 year prior to 
study entry AND no additional therapy is required during the study period
e) Subjects with a condition requiring systemic treatment with either corticosteroids (>10 
mg daily prednisone equivalent) or other immunosuppressive medications within 14 days 
of study drug administration. Inhaled or topical steroids and adrenal replacement steroid 
doses > 10 mg daily prednisone equivalent are permitted in the absence of active 
autoimmune disease. 
f)
Any serious or uncontrolled medical disorder or active infection that, in the opinion of 
the investigator, may increase the risk associated with study participation, study drug 
administration, or would impair the ability of the subject to receive protocol therapy
g) All toxicities attributed to prior anti-cancer therapy other than alopecia, fatigue, or 
peripheral neuropathy must have resolved to Grade 1 (NCI CTCAE version 4) or baseline 
before administration of study drug
h) As of Amendment 02, this criterion is no longer applicable. 
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3. Physical and Laboratory Test Findings
a) Any positive test result for hepatitis B virus or hepatitis C virus during screening 
indicating acute or chronic infection
b) As of Amendment 01, this criterion is no longer applicable. 
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. Sex and Reproductive Status
a) WOCBP who are pregnant or breastfeeding
b) Women with a positive pregnancy test at enrollment or prior to administration of study 
medication
6. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
A woman of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In 
addition, females under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level > 40 mIU/mL to confirm menopause.
Females treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. If the serum FSH level is > 40 mIU/mL at any time 
during the washout period, the woman can be considered postmenopausal:
•
1 week minimum for vaginal hormonal products (rings, creams, gels)
•
4 week minimum for transdermal products
•
8 week minimum for oral products
•
Other parenteral products may require washout periods as long as 6 months.
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3.5
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Subject’s request to stop study treatment
•
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject
•
Termination of the study by Bristol-Myers Squibb (BMS)
•
Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (eg, infectious disease) illness
•
Additional protocol specified reasons for discontinuation (Section 4.5.6)
All subjects who discontinue investigational product should comply with protocol-specified 
follow-up procedures. The only exception to this requirement is when a subject withdraws 
consent for all study procedures including post-treatment study follow-up or loses the ability to 
consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either a 
psychiatric or physical illness).
Subjects who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures (Table 5.1-4 and Table 5.1-5). The 
only exception to this is when a subject specifically withdraws consent for any further contact 
with him/her or persons previously authorized by subject to provide this information.
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In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate CRF page.
3.6
Post Study Drug Study Follow up
BMS may request that survival data be collected on all treated participants outside of the 
protocol-defined window (see Section 5.1, Flow Chart/Time and Events Schedule). 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.
In this study, safety is a key endpoint of the study. Post-study follow-up is of critical importance 
and is essential to preserving subject safety and the integrity of the study. Subjects who 
discontinue study drug must continue to be followed for collection of outcome and/or survival 
follow-up data as required and in line with Section 5 until death or the conclusion of the study.
The Follow-up Phase is described in Table 5.1-4 and Table 5.1-5. 
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In 
the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a Sponsor-
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retained third-party representative to assist site staff with obtaining subject’s contact information 
or other public vital status data necessary to complete the follow-up portion of the study. The site 
staff and representative will consult publicly available sources, such as public health registries 
and databases, in order to obtain updated contact information. If after all attempts, the subject 
remains lost to follow-up, then the last known alive date as determined by the investigator should 
be reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
•
nivolumab
•
ipilimumab
Premedications or medications used to treat infusion-related reactions should be sourced by the 
investigative sites if available and permitted by local regulations. Solution used as diluent 
solutions (0.9% sodium chloride injection, 5% dextrose injection) should also be sourced by 
investigative sites if available and permitted by local regulations.
In this protocol, investigational product(s) is/are: 
•
nivolumab
•
ipilimumab
In this protocol, non-investigational product(s) is/are: 
•
0.9% sodium chloride injection solution
•
5% dextrose injection solutions (diluents).
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined as a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be
considered as non-investigational products. 
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained 
that includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
4.3.1
Part I Study Drug Administration (Combination)
Subjects should receive nivolumab at a dose of 1 mg/kg as a 30-minute IV infusion, on Day 1 of 
each treatment cycle every 3 weeks for 4 doses or until progression, unacceptable toxicity, 
withdrawal of consent, or the study ends, whichever occurs first.
The nivolumab infusion must be promptly followed by a saline flush to clear the line of 
nivolumab before starting the next infusion.
The second infusion in the combination cohort will always be ipilimumab and will start at least 
30 minutes after the infusion line has been flushed, filters changed, and patient has been 
observed to ensure no infusion reaction has occurred. Subjects should receive ipilimumab at a 
dose of 3 mg/kg as a 30-minute IV infusion, on Day 1 of each treatment cycle every 3 weeks for 
4 doses or until progression, unacceptable toxicity, withdrawal of consent, or the study ends, 
whichever occurs first.
As of Amendment 04, all subjects will transition to the 30-minute infusion time for both 
nivolumab and ipilimumab.  
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4.3.2
Part II Study Drug Administration (Monotherapy)
Subjects should receive nivolumab at a dose of 3 mg/kg as a 30-minute IV infusion on Day 1 of 
each treatment cycle every 2 weeks until progression, unacceptable toxicity, or a maximum of 
24 months from the first dose of the combination regimen (Part I and II), whichever comes first. 
Subjects may be treated for more than 24 months for a maximum of 50 cycles in case an on-hold 
period occurs during the Treatment Phase.
At all sites who begin to enroll subjects after the implementation of Amendment 04, nivolumab 
will be administered at a dose of 240 mg IV every 2 weeks as a 30-minute infusion until 
progression, unacceptable toxicity, a maximum of 24 months from the first dose of the 
combination regimen (Part I and II), or the study ends, whichever comes first. Subjects may be 
treated for more than 24 months but for a maximum of 50 cycles in case an on-hold period 
occurs during the Treatment Phase.
4.4
Method of Assigning Subject Identification
After the subject’s initial eligibility is established and informed consent has been obtained, the 
subject must be enrolled into the study by calling an interactive voice response system (IVRS) to 
obtain the subject number. Every subject that signs the informed consent form must be assigned 
a subject number in IVRS. Specific instructions for using IVRS will be provided to the 
investigational site in a separate document. The investigator or designee will register the subject 
for enrollment by following the enrollment procedures established by BMS. The following 
information is required for enrollment:
•
Date that informed consent was obtained
•
Date of birth
•
Gender at birth
4.5
Selection and Timing of Dose for Each Subject
The dosing combination regimen and schedule for Parts I and II are detailed in Table 4.5-1 and
Table 4.5-2, respectively.
Table 4.5-1:
Dosing Schedule for Part I
Every 3 Week Dosing
One Cycle = 3 weeks
Cycle 1
Cycle 2
Cycle 3
Cycle 4
1 mg/kg nivolumab/
3 mg/kg ipilimumab
1 mg/kg nivolumab/
3 mg/kg ipilimumab
1 mg/kg nivolumab/
3 mg/kg ipilimumab
1 mg/kg nivolumab/
3 mg/kg ipilimumab
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Table 4.5-2:
Dosing Schedule for Part II
Every 2 Week Dosinga
1 Cycle = 2 weeks
Cycle 5b
Cycle 6
Cycle 7
Cycle 8 to Cycle 50 (last 
possible Cycle)
3 mg/kg nivolumab
Or
240 mg 
3 mg/kg nivolumab
Or
240 mg
3 mg/kg nivolumab
Or 
240 mg
3 mg/kg nivolumab
Or 
240 mg
a At sites who begin enrollment after the implementation of Amendment 04, nivolumab will be administered at a 
dose of 240 mg IV instead of 3 mg/kg. 
b Cycle 5 is to occur 3 weeks after Cycle 4. 
Ipilimumab may be diluted in 0.9% Sodium Chloride Solution or 5% Dextrose solution. 
Nivolumab may be diluted in 0.9% Sodium Chloride Solution or 5% Dextrose solution. 
Nivolumab 1 mg/kg will be infused over 30 minutes. After a 30-minute break between infusions, 
ipilimumab (3 mg/kg) will be infused over 30 minutes.
The dosing calculations should be based on body weight for subjects receiving nivolumab 
1 mg/kg and ipilimumab in Part I and 3 mg/kg in sites administering this dose in Part II. If the 
subject’s weight on the day of dosing differs by > 10% from the weight used to calculate the 
dose, the dose must be recalculated. All doses should be rounded up to the nearest milligram per 
institutional standard. There will be no dose modifications allowed.
During Part I, subjects may be dosed no less than 19 days between doses. If dosing is delayed, 
both nivolumab and ipilimumab must be delayed together. If dosing is resumed after a delay, 
both nivolumab and ipilimumab must be resumed on the same day. During Part II, subjects may 
be dosed no less than 12 days between doses. 
Subjects may be dosed up to 3 days after the scheduled date if necessary. Subsequent dosing 
should be based on the actual date of administration of the previous dose of drug.
4.5.1
Antiemetic Premedications
Antiemetic premedications should not be routinely administered prior to dosing of study drugs. 
See Section 4.5.7 for subsequent premedication recommendations following a nivolumab or 
ipilimumab-related infusion reaction. 
4.5.2
Dose Delay Criteria
Dose delay criteria apply for all drug-related AEs (regardless of whether or not the event is 
attributed to nivolumab, ipilimumab, or both). All study drugs must be delayed until treatment 
can resume (Section 4.5.5).
Nivolumab administration should be delayed for the following:
•
Any Grade 2 non-skin, drug-related adverse event, with the exception of fatigue
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•
Grade 2 drug-related creatinine, AST, ALT, and/or total bilirubin abnormalities
•
Grade 3 skin, drug-related adverse event
•
Grade 3 drug-related laboratory abnormalities with the following exceptions: 
−
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
−
Grade ≥ 3 AST, ALT, or total bilirubin will require dose discontinuation (see 
Section 4.5.6).
•
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 nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated and resume nivolumab dosing when re-treatment criteria are met.
The algorithms recommended for utilization are included in the nivolumab IB and Appendix 1 of 
this protocol.
See Section 4.5.5 for the maximum dosing delay. As described in Section 4.5.3, refer to the 
Investigator’s Brochure for management of AEs associated with immuno-oncology agents.
4.5.3
Management Algorithms for Immuno-Oncology Agents:
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
from AEs caused by other therapeutic classes. Nivolumab and ipilimumab are considered an I-O
agent in this protocol. Timely recognition and early management of adverse events associated 
with immuno-oncology agents may mitigate severe toxicity. BMS has adapted algorithms for use 
across immuno-oncology assets. These algorithms have led to successful resolution of toxicities 
with nivolumab monotherapy as well as in combination with ipilimumab. The algorithms are 
recommendations; there is flexibility to initiate more aggressive management when the 
investigator feels appropriate. Management algorithms can be found in Appendix 1 and have 
been developed to assist investigators in assessing and managing the following groups of AEs:
•
Pulmonary 
•
Gastrointestinal 
•
Endocrine
•
Hepatic 
•
Renal 
•
Skin 
Early intervention with corticosteroids or IMM may be instituted under this protocol upon the 
investigator’s clinical judgment. 
For subjects expected to require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an adverse event, consider recommendations provided in the 
Investigator’s Brochure.
While the ipilimumab Investigator Brochure contains safety 
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management algorithms for similar adverse events, the recommendations are to follow the 
nivolumab Investigator’s Brochure algorithms for I-O agents in order to standardize the safety 
management. 
4.5.4
Dose Modifications
Dose reductions and escalations are not permitted.
4.5.5
Criteria to Resume Treatment 
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to Grade ≤
1 or baseline value, with the following exceptions:
•
Subjects may resume treatment in the presence of Grade 2 fatigue 
•
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity 
•
For subjects with Grade 2 AST, ALT, or total bilirubin elevations, dosing may resume when 
laboratory values return to baseline and management with corticosteroids, if needed, is 
complete 
•
Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 4.5.6) should have treatment permanently discontinued
•
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed
•
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment. Adrenal insufficiency ≥
Grade 3
requires
discontinuation regardless of control with hormone replacement.
Subjects may resume treatment if the dose of systemic corticosteroids is 10 mg or less daily 
prednisone equivalent and immunosuppressive therapies (eg, infliximab) are not required. 
If the criteria to resume treatment are met, the subject should restart treatment at the next 
scheduled time point per protocol. However, if the treatment is delayed past the next scheduled 
time point per protocol, the cycle schedule will be revised to meet the dosing window 
requirements (ie, the next scheduled dose will occur at a minimum of 19 days in Part I and a 
minimum of 12 days in Part II after the re-initiation of dosing). See Section 4.5.2 for the 
maximum dosing delay.
If treatment is delayed > 12 weeks, the subject must be permanently discontinued from study 
therapy, except as specified in Section 4.5.6.
As described in Section 4.5.3, refer to the nivolumab Investigator’s Brochure for management of 
AEs associated with I-O agents.
During Part I, both nivolumab and ipilimumab should be resumed on the same day. However, if 
a nivolumab-related infusion reaction prevents subsequent infusion of ipilimumab on the same 
day, the dose of ipilimumab should be replaced as soon as possible. In such instances, at least 
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19 days must elapse between the replacement dose of ipilimumab and the administration of the 
next dose of nivolumab combined with ipilimumab. 
If both nivolumab and ipilimumab are discontinued during Part I due to an AE, a subject may 
begin nivolumab monotherapy (Part II) providing the following conditions are met:
•
The adverse event has resolved to Grade ≤1 or baseline within 12 weeks.
•
Subjects had no prior life-threatening AEs.
•
In investigator’s opinion, the subject may derive a clinical benefit from continuation of 
nivolumab monotherapy treatment.
•
Restrictions in Section 4.5.5, Criteria to Resume Treatment are met. 
•
Restrictions in Section 3.4, any concurrent antineoplastic therapy (ie, chemotherapy, 
hormonal therapy, immunotherapy, non-palliative radiation therapy, or standard or 
investigational agents for treatment of cancer) are met.
4.5.6
Discontinuation Criteria 
Discontinuation criteria apply for all drug-related AEs attributed to nivolumab, ipilimumab, or 
both. 
Nivolumab 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 uveitis, pneumonitis, bronchospasm, hypersensitivity reactions, infusion 
reactions, and endocrinopathies
−
Grade 3 drug-related diarrhea, colitis, neurologic toxicity, uveitis, pneumonitis, 
bronchospasm, myocarditis, hypersensitivity reaction, or infusion reaction of any 
duration requires discontinuation.
−
Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement.
−
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: 
•
Grade ≥ 3 drug-related AST, ALT, or total bilirubin requires discontinuation
NOTE: In most cases of Grade 3 AST or ALT elevation, study drugs will 
be permanently discontinued. If the investigator determines a possible 
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favorable benefit/risk ratio that warrants continuation of study drug(s), a 
discussion 
between 
the 
investigator 
and 
the
BMS 
Medical 
Monitor/designee must occur.
•
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
•
Any Grade 4 drug-related AE or laboratory abnormality, 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.
•
Any dosing interruption lasting > 12 weeks with the following exceptions:
−
Dosing interruptions to allow for prolonged steroid tapers to manage drug-related AEs
are allowed. 
−
Dosing interruptions > 12 weeks that occur for non-drug-related reasons may be allowed 
if approved by the BMS medical monitor. 
−
Prior to re-initiating treatment in a subject with a dosing interruption lasting > 12 weeks, 
the BMS medical monitor must be consulted. Tumor assessments should continue as per 
protocol even if dosing is interrupted.
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, presents a substantial clinical risk to the subject with continued nivolumab 
or ipilimumab dosing.
As described in Section 4.5.3, refer to the nivolumab Investigator’s Brochure for management of 
AEs associated with I-O agents.
4.5.7
Treatment of Nivolumab- or Ipilimumab-Related Infusion Reactions
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, they 
are unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if 
such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritis, 
arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion 
reactions should be reported within 24 hours to the BMS Medical Monitor and reported as an 
SAE if criteria are met. Infusion reactions should be graded according to NCI CTCAE 
(version 4.0) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate:
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generalized pruritus within 1 week after treatment), symptomatic treatment may be given 
(eg, oral antihistamine, or corticosteroids).
4.5.8
Treatment Beyond Disease Progression
As described in Section 1.1.5, accumulating evidence indicated a minority of subjects treated 
with immunotherapy may derive clinical benefit despite initial evidence of progressive disease 
(PD).53
Subjects treated with the study drugs will be permitted to continue treatment beyond initial PD as 
assessed by the investigator’s clinical judgment and local standards of care as long as they meet 
the following criteria:
•
Investigator-assessed clinical benefit and do not have rapid disease progression
•
Tolerance of study drug(s)
•
Stable performance status
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, central nervous system [CNS] metastases).
•
Subject provides written informed consent prior to receiving additional study treatment 
using an ICF describing any reasonably foreseeable risk or discomforts or other alternative 
treatment options
•
A radiographic assessment/scan should be performed within 6 weeks of original PD to 
determine whether there has been a decrease in the tumor size, stable disease, or continued 
PD. The assessment of clinical benefit should be balanced by clinical judgment as to 
whether the subject is clinically deteriorating and unlikely to receive any benefit from 
continued treatment.
For the subjects who continue study therapy beyond progression, further progression is defined 
as an additional 10% increase in tumor burden with a minimum 5 mm absolute increase 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 measurable at the time of initial progression if the longest diameter is 
at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). Any new lesion considered non-measurable at the time of initial progression may 
become measurable and therefore included in the tumor burden volume if the longest diameter 
increases to at least 10 mm (except for pathological lymph nodes which must have a short axis of 
at least 15 mm). In situations where the relative increase in total tumor burden by 10% is solely 
due to inclusion of new lesions which become measureable, these new lesions must demonstrate 
an absolute increase of at least 5 mm. 
Global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at the time should be reported as symptomatic deterioration. 
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Every effort should be made to document objective progression (ie, radiographic confirmation) 
even after discontinuation of treatment. 
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. All decisions to 
continue treatment beyond initial progression must be discussed in the study records, and 
subjects must sign a separate informed consent form to receive treatment beyond progression.
4.6
Blinding/Unblinding
Not applicable.
4.7
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF. 
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible Study Monitor will make 
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
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4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (CA209401)
Procedure
Screening
Visita
Notes
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion Criteria
X
Assessed at screening visit prior to any procedures and reassessed prior to first 
dose.
Medical History
X
Documentation of mutation status (BRAF, NRAS, cKIT) if considered standard of 
care or if otherwise known. 
Safety Assessments
Physical Examination
X
Included height, weight, ECOG PS. Focused physical exam performed at 
screening, if clinically indicated.
ECOG Performance Status
X
ECOG PS 0-1
ECOG PS 2
Vital Signs and Oxygen Saturation
X
Temperature, BP, RR, O2 saturation by pulse oxymetry at rest (also monitor 
amount of supplement oxygen if applicable). Obtain vital signs at screening visit 
and within 72 hours of first dose.
Serious Adverse Events Assessment
X
Adverse Events Assessment
X
No AE collection before first dose.
Assessment of Signs and Symptoms
X
After obtaining Informed Consent, assess all signs and symptoms within 14 days 
of first dose, prior to study treatment initiation. 
 
Laboratory Tests
X
Chemistry tests performed locally within 14 days prior to first dose (unless 
otherwise specified): CBC with differential, chemistry (BUN or serum urea level, 
creatinine, sodium, potassium, calcium, magnesium, phosphate, chloride, and 
glucose), AST, ALT, total bilirubin, alkaline phosphatase, albumin, LDH, TSH, 
free T3, free T4, and lipase. Within 28 days prior to first dose, hepatitis B surface 
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Table 5.1-1:
Screening Procedural Outline (CA209401)
Procedure
Screening
Visita
Notes
antigen (HBsAg) and hepatitis antibody (HCV Ab). 
Pregnancy Tests 
X
Performed within 24 hours prior to first dose for WOCBP only (serum or urine as 
required by the standard of care at the site). An extension of up to 72 hours prior to 
the first dose of nivolumab and ipilimumab is permissible in situations where 
results cannot be obtained within the standard 24 hour window. See Section 3.3.3
for the definition of Women of Childbearing Potential 
Tumor Tissue Sample
X
May be archival. 1 paraffin block or a minimum of 10 FFPE unstained slides 
received by Central Lab prior to subject enrollment. (FNA and bone metastases 
samples not acceptable)
Additional Assessments 
 
Efficacy Assessments
Screening/Baseline Tumor Assessments
X
Chest, abdomen, pelvis, brain, and other known sites of disease within 6 weeks of 
the first dose of study therapy. Subjects must have evaluable disease by CT or 
MRI per RECIST 1.1 criteria (radiographic tumor assessment performed within 
6 weeks prior to first dose of study) or clinically apparent disease that the 
investigator to follow for response. 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; BUN, blood urea nitrogen; CBC, complete blood count; CT, computerized 
tomography; ECOG, Eastern Cooperative Oncology Group; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire; HBsAg, hepatitis B surface antigen; HCV Ab, hepatitis C antibody; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; O2, oxygen; 
PS, Performance Status; RECIST, Response Evaluation Criteria in Solid Tumors; RR, respiratory rate; TSH, thyroid stimulating hormone; WOCBP, women of 
child bearing potential 
a Within 28 days ± 5 days before start of nivolumab and ipilimumab combination regimen 
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Table 5.1-2:
On Study Assessments Part I: Cycles 1 Through 4 (Nivolumab Plus Ipilimumab)a
Procedure
Every Cycle 
(Every 3 weeks)
Every 2 Cycles 
(Every 6 Weeks)
Notes
Efficacy Assessments
Tumor Scans
---See notes---
Initial tumor assessment, utilizing RECIST 1.1 criteria, is to be completed at 
Week 12 (±5 days). Further tumor assessments are recommended to be 
completed as required by local standards of care or at the investigator 
discretion and are recommended every 8 weeks. 
Outcomes Assessments 
Clinical Drug Supplies
Administration of Study Drug
X
a If a dose is delayed, the procedures scheduled for that same time point should also be delayed to coincide with when that time point’s dosing actually occurs.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; BUN, blood urea nitrogen; CBC, complete blood count; ECOG, Eastern 
Cooperative Oncology Group; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; HR, heart rate; 
LDH, lactate dehydrogenase; LFT, liver function test; NCI CTCAE, National Cancer Institute Common Terminology Criteria for AEs; O2, oxygen; PS,
Performance Status; NCI CTACE, National Cancer Institute Common Terminology Criteria for Adverse Events; RECIST, Response Evaluation Criteria in Solid 
Tumors; RR, respiratory rate; TSH, thyroid stimulating hormone; TFT, thyroid function test.
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Table 5.1-3:
On-Treatment Assessments Part II: Cycles 5 and Beyond (Nivolumab Monotherapy)a,b
Procedure
Every Cycle 
(Every 2 weeks)
Every 2 Cycles 
(Every 4 weeks)
Every 3 Cycles 
(Every 6 weeks)
Every 4 Cycles 
(Every 8 weeks)
Notes
Clinical Drug 
Supplies
Administration of 
Study Drug
X
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; BUN, blood urea nitrogen; CBC, complete blood count; ECOG, Eastern 
Cooperative Oncology Group; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; HR, heart rate; 
LDH, lactate dehydrogenase; LFT, liver function test; NCI CTCAE, National Cancer Institute Common Terminology Criteria for AEs; O2, oxygen; PS,
Performance Status; NCI CTACE, National Cancer Institute Common Terminology Criteria for Adverse Events; RECIST, Response Evaluation Criteria in Solid 
Tumors; RR, respiratory rate; TSH, thyroid stimulating hormone; TFT, thyroid function test.
a If a dose is delayed, the procedures scheduled for that same time point should also be delayed to coincide with when that time point’s dosing actually occurs.
b Cycle 5 begins 3 weeks after Cycle 4.
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Table 5.1-4:
Follow Up Assessments for Subjects who Discontinue in Part Ia
Procedure
Every 4 Weeks (±7 days) through 
100 Days after last dose of study 
drug
Notes
Safety Assessments 
Physical Exams
X
Collect weight and ECOG PS. Focused physical examination may be 
performed if clinically indicated and to assess for potential late emergent 
study drug related issues.
Vital signs and Oxygen Saturation
X
Temperature, BP, HR, RR, O2 saturation by pulse oximetry at rest (also 
monitor amount of supplemental oxygen if applicable) at any time a subject
has any new or worsening respiratory symptoms.
Adverse Event Assessment
X
All nonserious AEs (not only those deemed to be treatment-related) should be 
collected continuously during the treatment period and for a minimum of 100 
days following the last dose of study treatment. Nonserious AEs should be 
followed to resolution to stabilization or reported as SAEs if they become 
serious.
Serious Adverse Event Assessments
X
All SAEs that occur during the screening period and within 100 days of 
discontinuation of dosing must be collected. 
Laboratory Tests: CBC with 
differential 
X
Includes WBC, lymphocytes, ANC, hemoglobin, hematocrit, platelet count.
Laboratory Tests: chemistry tests
X
Includes BUN or serum urea, creatinine, sodium, potassium, calcium, 
magnesium, phosphate, chloride, glucose, amylase, lipase, and LDH.
Laboratory Tests: Liver function tests
X
Includes AST, ALT, total bilirubin, alkaline phosphate, albumin
Efficacy Assessments
Subject survival status
---see notes---
May be accomplished by visit for the first 100 days and then by visit or 
phone for up to 2 years from the first dose of combination regimen therapy
Laboratory Tests: Thyroid function 
tests
X
Includes TSH (reflect to free T3 and free T4 if abnormal results)
Tumor scans 
---see notes---
Tumor progression scans are recommended to be completed as required by 
local standards of care or at the investigator’s discretion for up to 2 years.
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5.1.1
Retesting During Screening Period
Retesting of laboratory parameters and/or other assessments within any single Screening period 
will be permitted (in addition to any parameters that require a confirmatory value).
Any new result will override the previous result (ie, the most current result prior to 
administration) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 5.1-1 may be repeated in an 
effort to find all possible well-qualified subjects. Consultation with the Medical Monitor may be 
needed to identify whether repeat testing of any particular parameter is clinically relevant.
5.2
Study Materials
The site will provide:
•
all required materials for the tests performed locally (ie, relevant to clinical laboratory tests)
•
a well-calibrated scale for recording body weight
•
a calibrated sphygmomanometer, and thermometer for vital sign assessments
•
a monitored refrigerator
•
all materials required for accurate source documentation of study activities. 
BMS will provide:
•
IVRS manual
•
Nivolumab Investigator’s Brochure and Ipilimumab Investigator’s Brochure
•
a BMS-approved protocol and any amendments or administrative letters (if required)
•
case report forms (electronic or hard copy)
•
nivolumab and ipilimumab
•
validated and translated version of the EORTC QLQ-C30
•
Pharmacy binder and pharmacy reference sheets
5.3
Safety Assessments
At baseline, a medical history will be obtained to capture relevant underlying conditions and 
mutation status. The baseline examinations should include weight, height, ECOG Performance 
Status, and should be performed within 28 days prior to first dose. Baseline signs and symptoms 
are those that are assessed within 14 days prior to first dose. Concomitant medications will be 
collected from within 14 days prior to the first dose through the study treatment period. Vital 
signs including temperature, blood pressure (BP), respiration rate, and oxygen saturation should 
be collected within 72 hours of first dose (see Table 5.1-1). A pregnancy test should be 
performed within 24 hours prior to first dose for WOCBP only (serum or urine as required by the 
standard of care at the site). An extension of up to 72 hours prior to the first dose of nivolumab 
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and ipilimumab is permissible in situations where pregnancy test results cannot be obtained 
within the standard 24 hour window.
Baseline local laboratory assessments should be done within 14 days prior to the first dose and 
include: CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), albumin, 
BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, phosphate, glucose, lipase, TSH, 
Free T4, and Free T3. Hep B and C testing (HBV sAg and HCV RNA or Ab) should be done 
within 28 days prior to first dose. 
The following safety assessments should be monitored every cycle, except where noted, starting 
with dosing until approximately 100 days following the discontinuation from study therapy, 
providing AEs have resolved:
•
AEs continuously throughout the study
•
Physical examination and physical measurements including weight and ECOG performance 
status
•
Complete blood counts (CBCs) with differential, including WBC, lymphocyte count, ANC, 
hemoglobin, hematocrit, and platelet count. Laboratory tests should be completed and 
reviewed within 72 hours prior to dosing.
•
Chemistry tests (BUN or serum urea level, creatinine, sodium, potassium, calcium, 
phosphate, chloride, magnesium, glucose, amylase, lipase, and LDH). Laboratory tests 
should be completed with 72 hours and reviewed prior to dosing. If sites are unable to 
obtain lipase results prior to dosing, dosing may still occur provided all other safety 
laboratory results including amylase are available and reviewed by the investigator prior to 
dosing.
•
Liver function tests including AST, ALT, total bilirubin, alkaline phosphatase, albumin. 
Laboratory tests should be completed within 72 hours and reviewed prior to dosing.
•
Thyroid function testing, including TSH (reflex to free T3 and free T4 if abnormal results), 
to be completed every 6 weeks. Laboratory tests should be completed within 72 hours and 
reviewed prior to dosing. 
•
Concomitant medications will be collected at the screening visit, throughout the study 
treatment period, and follow up. 
Subjects will also receive a weekly phone call to report AEs on the weeks without study visits. 
Follow up begins when the decision to discontinue study therapy is made (no further treatment 
with study drug) and is described in Table 5.1-4 and Table 5.1-5:
•
Subjects who discontinue therapy in Part I are recommended to be followed by direct 
contact (office visit) every 4 weeks for up to 100 days after the last dose of regimen therapy. 
After completion of the onsite follow-up visits (for up to 100 days), subjects will be 
followed every 24 weeks ± 2 weeks for survival either by onsite visit or via telephone. OS 
will be followed from the start of therapy up to 2 years or until death, withdrawal of study 
consent, or lost-to-follow-up, whichever comes first.
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•
For subjects who complete or discontinue therapy in Part II, subjects will have 2 follow-up 
visits (office visits): one approximately 30 days after the last dose of study drug and one 
approximately 100 days after the last dose of study drug. After completion of the first 2 
follow-up visits, subjects will be followed every 24 weeks ± 2 weeks for survival either by 
visit or phone. OS will be followed from the start of therapy up to 2 years (+ 100 days 
following the last dose of study treatment), or until death, withdrawal of study consent, or 
lost-to-follow-up, whichever comes first.
•
For subjects who complete therapy in Part II (2 years of treatment), subjects will have 2 
follow-up visits (office visits): one approximately 30 days after the last dose of study drug 
and one approximately 100 days after the last dose of study drug. 
5.3.1
Imaging Assessment for the Study
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.
5.4
Efficacy Assessments
Efficacy assessments include an initial tumor assessment at Week 12 (± 5 days) after first 
combination dose. Further tumor assessments are to be completed as required by local standards 
of care or at the investigator’s discretion and are recommended every 8 weeks, as discussed in 
Table 5.1-2 and Table 5.1-3. Subjects will be followed for survival status in accordance with 
Table 5.1-4 and Table 5.1-5 for up to 2 years following the start of therapy (+ 100 days following 
the last dose of study treatment), or until death, withdrawal of study consent, or lost-to-follow-
up, whichever comes first (see Section 5.3).
Study evaluations will take place in accordance with Table 5.1-2 and Table 5.1-3.
High resolution CT with oral or IV contrast or contrast-enhanced MRI are the preferred imaging 
modalities for assessing radiographic tumor response. If a subject has a known allergy to contrast 
material, please use local prophylaxis standards to obtain the assessment with contrast if at all 
possible or use an alternate modality. In cases where contrast is strictly contraindicated, a 
non-contrast scan will suffice. Screening assessments should be performed within 6 weeks of 
first dose of study drug. Brain MRI is the preferred imaging method for evaluating CNS 
metastasis, and an assessment is required during screening in subjects with a known history of 
treated brain metastases. All known or suspected sites of disease (including CNS) should be 
assessed at screening and at subsequent assessments using the same imaging method and 
technique. If more than one method is used at screening, then the most accurate method (with 
RECIST 1.1 as the preferred method) should be used when recording data and should again be 
used for all subsequent assessments. Bone scan, PET scan, or ultrasound is not adequate for 
assessment of RECIST response. In selected circumstances where such modalities are the sole 
modality used to assess certain non-target organs, those non-target organs may be evaluated less 
frequently. For example, bone scans may need to be repeated only when complete response is 
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identified in the target disease or when progression in bone is suspected. Previously treated CNS 
metastases are not considered measurable lesions for purposes of RECIST determined response.
Tumor measurements should be made by the same investigator or radiologist for each 
assessment whenever possible. Changes in tumor measurements and tumor responses to guide 
ongoing study treatment decisions should be assessed by the investigator.
5.4.1
Target Lesions
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should lend themselves to reproducible repeated 
measurements.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted below, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
Previously treated CNS metastases are not considered measurable lesions for purposes of 
RECIST 1.1 determined response.
5.4.1.1
Lymph Nodes
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
Nodes that have a short axis < 10 mm are considered non-pathological and should not be 
recorded or followed.
5.4.1.2
Non-Target Lesions
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present,’ ‘absent,’ or in rare cases ‘unequivocal 
progression.’ In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’).
5.4.2
Tumor Response Evaluation
5.4.2.1
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.
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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.
5.4.2.2
Target Lesions that Become “Too Small to Measure”
All lesions (nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (eg, 2 mm). If the radiologist is 
able to provide an actual measurement, that should be recorded, even if it is below 5 mm.
5.4.2.3
Target Lesions that Split or Coalesce on Treatment
When non-nodal lesions ‘fragment,’ the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum
As lesions coalesce, a plane between them maybe 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’
5.4.2.4
Evaluation of Non-Target Lesions
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol.
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be non-
pathological in size (< 10 mm short axis).
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) above the normal limits.
Progressive Disease (PD): Unequivocal progression of existing non-target lesions (Note: the 
appearance of one or more new lesions is also considered progression).
5.4.3
Unequivocal Progression in Non-Target Disease
To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD or 
PR in target disease, the overall tumor burden has increased sufficiently to merit discontinuation 
of therapy.
A modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to 
qualify for unequivocal progression status
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5.4.4
New Lesions
The appearance of new malignant lesions denotes disease progression. The finding of a new 
lesion should be unequivocal: ie, not attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumor (for example, 
some ‘new’ bone lesions may be simply healing or flare of preexisting lesions). This is 
particularly important when the subject’s baseline lesions show partial or complete response. For 
example, necrosis of a liver lesion may be reported on a CT scan reported as a ‘new’ cystic 
lesion, which it is not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the subject who has visceral disease at baseline and while on study has a CT or MRI brain scan 
ordered which reveals metastases. The subject’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.8
Other Assessments 
Not applicable. 
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The causal relationship can be one of the following:
•
Related: There is a reasonable causal relationship between study drug administration and the 
AE.
•
Not related: There is not a reasonable causal relationship between study drug administration 
and the AE.
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
BMS will be reporting AEs to regulatory authorities and ethics committees according to the local 
applicable laws including European Directive 2001/20/EC and FDA Code of Federal 
Regulations 21 CFR Parts 312 and 320 
For EEA countries the following will apply, unless alternative reporting modalities and 
mandated by local laws / guidelines: 
•
Investigator to report SAEs immediately (24 hrs) to sponsor. NSAE as per protocol 
specification. 
•
Sponsor records SAEs and AEs in a central database 
•
Sponsor to report SUSARs to HA, EC within 15 days (7 days for death / life threatening), 
unless local law / guidelines specify otherwise 
•
Sponsor to inform investigators of SUSARs in aggregate format (unless agreed otherwise) 
•
Annual Safety reports submitted to HA and EC 
•
SUSARs are submitted to EV from the EU PV Office in Braine. 
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•
Impact on B/R shall be communicated in accordance with Directive 2001/20EC 
For USA, requirements of FDA Code of Federal Regulations 21 CFR apply and for other 
countries safety reporting will be in accordance with local laws / guidelines. 
Suspected Unexpected Serious Adverse Reaction is a serious adverse event that is both 
unexpected and related to an IMP or comparator IMP, for which expedited reporting to clinical 
investigators, Ethics Committees and Health Authorities is required (Previously known as ESR).
Immune-mediated adverse events (IMAEs) 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.
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
•
results in death
•
is life-threatening (defined as an event in which the subject was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)
•
requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below)
•
results in persistent or significant disability/incapacity
•
is a congenital anomaly/birth defect 
•
is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.) Potential drug induced liver injury (DILI) is also considered an 
important medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See 
Section 6.1.1 for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
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NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
−
a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event)
−
elective surgery, planned prior to signing consent
−
admissions as per protocol for a planned medical/surgical procedure
−
routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy)
−
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
−
admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason).
−
Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 100 days of discontinuation of dosing.
For subjects that are enrolled and never treated with study drug, report all SAEs that occur 
during the screening period and within 30 days of the date of enrollment.
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS (or 
designee) within 24 hours of awareness of the event. SAEs must be recorded on the SAE Report 
Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The preferred 
method for SAE data reporting collection is through the eCRF. The paper SAE/pregnancy 
surveillance forms are only intended as a back-up option when the eCRF system is not 
functioning. In this case, the paper forms are to be transmitted via email or confirmed facsimile 
(fax) transmission to:
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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, 
The paper forms should be used and submitted immediately, paper forms are used and submitted 
immediately. When the paper forms are used, the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
BMS will be reporting adverse events to regulatory authorities and ethics committees according 
to local applicable laws including European Directive 2001/20/EC and FDA Code of Federal 
Regulations 21 CFR Parts 312 and 320. 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.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects. All nonserious AEs 
(not only those deemed to be treatment-related) should be collected continuously during the 
treatment period and for a minimum of 100 days following the last dose of study treatment.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 
as appropriate. All identified nonserious AEs must be recorded and described on the nonserious 
AE page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:
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•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted
•
Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 5 
half lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough 
discussion of benefits and risk with the subject 
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
of awareness of the event and in accordance with SAE reporting procedures described in 
Section 6.1.1. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details.).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
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Potential drug induced liver injury is defined as: 
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
6.7
Other Safety Considerations
Any 
significant 
worsening
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
The Scientific Steering Committee (SSC) will closely review the safety data throughout the 
study to evaluate the risk/benefit ratio in general and for the separate prospective PS2 subgroup
and for subjects treated by ipilimumab monotherapy experienced investigators following a
predefined Safety Management Plan.
Safety Management Plan will include but not be limited to the following frequency and will be 
triggered by treated patients with ECOG PS-2 
•
Safety review: Safety review for all treated patients will take place when a minimum of 10 
patients in ECOG PS2 subgroup have been dosed with at least 6 weeks of combination 
regimen therapy (nivolumab combined with ipilimumab) on study to assess safety in all 
subgroups and evaluate further enrollment into PS2 subgroup.
•
Safety review: Safety review for all treated patients will take place when a minimum of 10 
patients with at least 12 weeks of combination regimen therapy (nivolumab combined with 
ipilimumab) on study to assess safety in all subgroups.
•
Subsequent safety reviews: According to the results of previous reviews, further monitoring 
and subsequent assessments and evaluation of safety will be conducted on a 12-week 
schedule and data will be provided.
The following data will be provided for safety review:
•
Treatment-related AEs with focus on:
−
Drug-related SAEs in all subgroups
−
Immune-mediated, select adverse events: all grades in all treated patients
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−
AEs leading to discontinuation
−
All treatment-related deaths
•
ECOG performance status over time
If unexpected events occur, ad hoc telephone conferences with the SSC will be set up.
Review for risk/benefit assessment will be performed for all treated subjects. Initial review for 
the ECOG 0-1 subgroups is planned for the first 100 subjects who have been in the study for at 
least 6 months on study and should contain following parameters:
•
Efficacy:
−
Response (based on initial tumor assessment) and overall clinical benefit
−
Symptomatic improvement
−
Survival benefit 
•
Safety:
−
Incidence (rate) and outcomes (time to and grade of resolution) of Grades 3-5, treatment-
related AEs
−
Duration of immunosuppressant therapy for IMAE management
−
Change in ECOG Performance status over time
According to the results of the safety and risk/benefit reviews, further ones will be conducted on 
an as needed basis, and data will be provided.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
Of 768 subjects who will be screened to receive first-line therapy for advanced disease with 
histologically confirmed stage III (unresectable) or stage IV melanoma, approximately 
615 subjects will be treated with nivolumab and ipilimumab regimen. This sample size is based 
on the primary objective of the study: determining the incidence of high-grade (CTCAE v4.0 
Grades 3-5), treatment-related, select adverse events of potentially immune-mediated etiology in 
subjects receiving first-line therapy for advanced disease. The sample size will allow for 
estimating an incidence of about 50% with a 95% CI of (46.06%, 54.11%) under 308 subjects 
with events among 615 treated subjects.  
8.2
Populations for Analyses
•
All enrolled subjects: all subjects who sign an informed consent form and are registered into 
the IVRS.
•
All treated subjects: all subjects who receive any dose of study medicine. This is the primary 
population for safety and efficacy analyses.
•
All response evaluable subjects: all treated subjects who have baseline and at least one 
on-study evaluable tumor measurement.
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nivolumab
8.4
Analyses
Descriptive statistics will be presented for each of the endpoints. The analysis of primary, 
secondary, and exploratory endpoints will be reported for the full safety analysis set (all treated 
subjects) and by subgroups based on ECOG PS, brain metastasis, ocular and mucosal melanoma, 
and investigator experience in treating with the nivolumab plus ipilimumab combination 
regimen.
8.4.1
Demographics and Baseline Characteristics
Demographics characteristic and disease characteristics at baseline will be summarized using 
descriptive statistics for all treated subjects and by cohort.
8.4.2
Efficacy Analyses
8.4.2.1
Secondary Analyses 
OS will be summarized by Kaplan-Meier method for all treated subjects and by cohort. Median 
values of OS, along with 2-sided 95% CI using Brookmeyer and Crowley method, will be 
calculated.
The investigator-assessed ORR will be summarized by binomial response rates and their 
corresponding 2-sided 95% exact CIs using the Clopper-Pearson method. This analysis will be 
performed for all response evaluable subjects and by subgroup. The DOR will be summarized 
for subjects who achieve confirmed PR or CR using the Kaplan-Meier method. Median values of 
DOR, along with 2-sided 95% CI using Brookmeyer and Crowley method, will also be 
calculated.
The abovementioned OS, investigator-assessed ORR, and safety and tolerability will be 
conducted specifically for subjects with Performance Status 2, ocular or mucosal melanoma.
 
 
 
 
8.4.3
Safety Analyses
8.4.3.1
Primary Analyses
The number and percentage of subjects who report high-grade (Grade 3-5), treatment-related, 
select adverse events of potentially immune-mediated etiology will be summarized for all treated 
subjects overall. High-grade (Grade 3-5), treatment-related select adverse events will be 
tabulated using worst grade per CTCAE v4.0 criteria by system organ class and Medical 
Dictionary for Regulatory Affairs (MedDRA) preferred term.
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8.4.3.2
Secondary Analyses
The number and percentage of subjects who report high-grade (Grade 3-5), treatment-related, 
select adverse events of potentially immune-mediated etiology will be summarized for all treated 
subjects overall and by subgroup. High-grade (Grade 3-5), treatment-related, select adverse 
events will be tabulated using worst grade per CTCAE v4.0 criteria by system organ class and 
Medical Dictionary for Regulatory Affairs (MedDRA) preferred term. Time to onset and 
resolution of the events, dose of immune-modulating medications subjects received for the 
events, and the event by grade will also be tabulated for all treated subjects and by subgroups. 
Cumulative doses of immune-modulating agents will be summarized and reported.
All safety data will be listed and tabulated for all treated subjects. All AEs, treatment-related 
AEs, serious AEs, deaths, and select AEs such as pulmonary, gastrointestinal, skin, renal, 
hepatic, endocrine, infusion-related, or hypersensitivity will be summarized by system organ 
class and preferred term, and coded according to the most current version of MedDRA.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.4.7
Other Analyses 
Not applicable. 
8.5
Interim Analyses
Not applicable. 
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC and Regulatory Authority(ies), if required by local regulations, of an 
amendment, except where necessary to eliminate an immediate hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:
•
IRB/IEC for review and approval/favorable opinion
•
BMS
•
Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
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 BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
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nivolumab
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or 
entered electronically. If source data are created (first entered), modified, maintained, archived, 
retrieved, or transmitted electronically via computerized systems (and/or any other kind of 
electronic devices) as part of regulated clinical trial activities, such systems must be compliant 
with all applicable laws and regulations governing use of electronic records and/or electronic 
signatures. Such systems may include, but are not limited to, electronic medical/health records 
(EMRs/EHRs), adverse event tracking/reporting, protocol required assessments, and/or drug 
accountability records).
When paper records from such systems are used in place of electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of a 
copy of original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include investigational product and 
the following non-investigational product(s): NA. 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
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nivolumab
•
label identification number or batch number 
•
amount dispensed to and returned by each subject, including unique subject identifiers
•
amount transferred to another area/site for dispensing or storage
•
nonstudy disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for bioavailability/bioequivalence, if applicable
•
dates 
and 
initials 
of 
person 
responsible 
for 
Investigational 
Product 
dispensing/accountability, as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be 
left blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator 
and who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review 
and approval/signature is completed electronically through the BMS electronic data capture tool.
The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
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9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the 
following criteria:
•
External Principal Investigator designated at protocol development
•
Study Steering Committee chair or their designee
•
Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study must adhere to the publication requirements set forth in the 
clinical trial agreement (CTA) governing [Study site or Investigator] participation in the study. 
These requirements include, but are not limited to, submitting proposed publications to BMS at 
the earliest practicable time prior to submission or presentation and otherwise within the time 
period set forth in the CTA.
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10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If one form of contraception is required, Complete 
Abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Female subjects must continue to have 
pregnancy tests. Acceptable alternate methods of highly 
effective contraception must be discussed in the event that 
the subject chooses to forego complete abstinence.
If two forms of contraception is required, Complete 
abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence.
Expanded definition Complete abstinence as defined as 
complete avoidance of heterosexual intercourse is an 
acceptable form of contraception for all study drugs. This 
also means that abstinence is the preferred and usual lifestyle 
of the patient. This does not mean periodic abstinence (e.g., 
calendar, ovulation, symptothermal, profession of abstinence 
for entry into a clinical trial, post-ovulation methods) and 
withdrawal, which are not acceptable methods of 
contraception. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence
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11
LIST OF ABBREVIATIONS
Term
Definition
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
CBC
complete blood count
CI
confidence interval
CNS
Central nervous system
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HR
heart rate
HRT
hormone replacement therapy
ICH
International Conference on Harmonisation 
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nivolumab
Term
Definition
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug 
I-O
Immuno-oncology agents
IRB
Institutional Review Board
IV
intravenous
kg
kilogram
LDH
lactate dehydrogenase
mg
milligram
min
minute
mL
milliliter
mmHg
millimeters of mercury
MTD
maximum tolerated dose
N
number of subjects or observations
Na+
sodium
N/A
not applicable
NIMP
non-investigational medicinal products 
RBC
red blood cell
SAE
serious adverse event
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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SAP_001.pdf: 
Official Title of Study: 
CLINICAL TRIAL OF NIVOLUMAB (BMS-936558) COMBINED WITH IPILIMUMAB 
FOLLOWED BY NIVOLUMAB MONOTHERAPY AS FIRST-LINE THERAPY OF 
SUBJECTS WITH HISTOLOGICALLY CONFIRMED STAGE III (UNRESECTABLE) 
OR STAGE IV MELANOMA 
 
 
NCT Number: NCT02599402 
Document Date (Date in which document was last revised): February 25, 2020 
 






St atisti c al  A n al ysis  Pl a n  v 2. 1 
C A 2 0 9 4 0 1 
B M S- 9 3 6 5 5 8 
Ni v ol u m a b 
 
3 
6. 4  
S u b gr o u ps f or  A n al ys es .............................................................................................. 1 6  
7  
S T A TI S TI C A L  A N A L Y S E S ..................................................................................... 1 6  
7. 1  
G e n er al  M et h o ds ......................................................................................................... 1 6  
7. 2  
St u d y  C o n d u ct ............................................................................................................ 1 6  
7. 2. 1  
A c cr u al ....................................................................................................................... . 1 6 
7. 2. 2  
R el e v a nt  Pr ot o c ol  D e vi ati o ns ..................................................................................... 1 7  
7. 3  
St u d y  P o p ul ati o n ......................................................................................................... 1 7  
7. 3. 1  
S u bj e ct  Dis p ositi o n ..................................................................................................... 1 7  
7. 3. 2  
D e m o gr a p hi c  a n d  B as eli n e  C h ar a ct eristi cs ............................................................... 1 7  
7. 3. 3  
M e di c al  Hist or y .......................................................................................................... 1 8  
7. 3. 4  
Pri or  C a n c er  T h er a p y ................................................................................................. 1 8  
7. 3. 5  
B as eli n e  E x a mi n ati o ns ................................................................................................ 1 9  
7. 4  
E xt e nt  of  E x p os ur e ..................................................................................................... 1 9  
7. 4. 1  
A d mi nistr ati o n  of  St u d y  T h er a p y ................................................................................ 1 9  
7. 4. 2  
M o difi c ati o ns  of  St u d y  T h er a p y .................................................................................. 2 0  
7. 4. 2. 1  
D os e  D el a ys ................................................................................................................ 2 0  
7. 4. 2. 2  
I nf usi o n I nt err u pti o ns  a n d  R at e  C h a n g es ................................................................... 2 0 
7. 4. 2. 3  
D os e  Es c al ati o ns ........................................................................................................ 2 0  
7. 4. 2. 4  
D os e  R e d u cti o ns ......................................................................................................... 2 0  
7. 4. 2. 5  
D os e  O missi o ns .......................................................................................................... 2 0  
 
 
7. 5  
Effi c a c y ...................................................................................................................... . 2 1 
7. 5. 1  
S e c o n d ar y  A n al ys es .................................................................................................... 2 1  
7. 5. 2  
S ur vi v al ...................................................................................................................... . 2 1 
7. 5. 3  
O bj e cti v e  R es p o ns e  R at e ............................................................................................. 2 1  
7. 5. 4  
D ur ati o n  of  O bj e cti v e  R es p o ns e ................................................................................. 2 1  
 
 
7. 6  
S af et y ........................................................................................................................ .. 2 2 
7. 6. 1  
Pri m ar y  A n al ys es ........................................................................................................ 2 2  
7. 6. 1. 1  
Hi g h  Gr a d e  Tr e at m e nt- R el at e d  S el e ct  A d v ers e  E v e nts  of  P ot e nti all y I m m u n e-
M e di at e d  Eti ol o g y ....................................................................................................... 2 2  
7. 6. 2  
S e c o n d ar y  A n al ys es .................................................................................................... 2 2  
A p p r o v e d  
1 . 0
v


St atisti c al  A n al ysis  Pl a n  v 2. 1 
C A 2 0 9 4 0 1 
B M S- 9 3 6 5 5 8 
Ni v ol u m a b 
 
4 
7. 6. 2. 1  
Hi g h  Gr a d e  Tr e at m e nt- R el at e d  S el e ct  A d v ers e  E v e nts  of  P ot e nti all y I m m u n e-
M e di at e d  Eti ol o g y i n  R el e v a nt  S u b gr o u ps ................................................................. 2 2  
7. 6. 2. 2  
S el e ct  A d v ers e  E v e nts  of  P ot e nti all y I m m u n e- M e di at e d  Eti ol o g y .............................. 2 2  
7. 6. 2. 3  
I m m u n e- M o d ul ati n g  M e di c ati o ns ............................................................................... 2 2 
7. 6. 3  
Ot h er  S af et y  A n al ys es ................................................................................................. 2 2  
7. 6. 4  
A d v ers e  E v e nts  b y  St a n d ar diz e d  M e d D R A  Q u er y ( S M Q) .......................................... 2 3  
 
 
 
 
 
 
8  
C O N V E N TI O N S ........................................................................................................ 2 5  
9  
C O N T E N T  O F  R E P O R T S ......................................................................................... 2 5  
9. 1  
Cli ni c al  St u d y  R e p ort ................................................................................................. 2 5  
9. 2  
Ot h er  R e p orts  a n d  R e vi e ws ........................................................................................ 2 5  
9. 2. 1  
S af et y  R e vi e ws ............................................................................................................ 2 5  
 
 
1 0  
D O C U M E N T  HI S T O R Y ........................................................................................... 2 6  
A P P E N DI X  1  
S E L E C T  A D V E R S E  E V E N T S  D E FI NI TI O N  A N D 
C O N V E N TI O N S ....................................................................................... 2 8  
 
 
LI S T  O F  T A B L E S 
T a bl e  2. 1- 1:  
Tr e at m e nt  P h as e:  D osi n g  S c h e d ul e f or  P art I .............................................. 8  
T a bl e  2. 1- 2:  
Tr e at m e nt  P h as e:  D osi n g  S c h e d ul e f or  P art II ............................................. 8  
T a bl e  2. 4- 1:  
Pr ot o c ol  A m e n d m e nts .................................................................................. 9  
T a bl e  4. 2. 4- 1:               C e ns ori n g  S c h e m e  Us e d i n t h e  A n al ysis  of  P F S ....................................... 1 3  
T a bl e  7. 4. 1- 1:               St u d y  T h er a p y  P ar a m et er  D efi niti o ns ....................................................... 1 9  
T a bl e  A- 1:  
D eri v ati o n  of  cl ust er e d s el e ct  A E .............................................................. 2 9  
T a bl e  A- 2:  
S el e ct  A d v ers e  E v e nts................................................................................ 3 1  
 
A p p r o v e d  
1 . 0
v














































St atisti c al  A n al ysis  Pl a n  v 2. 1 
C A 2 0 9 4 0 1 
B M S- 9 3 6 5 5 8 
Ni v ol u m a b 
 
2 7 
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D at e  of  C h a n g es 
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2. 1 
 
2 7J a n 2 0 2 0 
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2. 1 
 
3 1J a n 2 0 2 0 
T h e s u b gr o u ps  of  w ei g ht- b as e d  vs. fl at 
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r e m o v e d fr o m  a n al ys es,  as t h e y  ar e  n ot 
s p e cifi e d i n t h e  pr ot o c ol. 
2. 1 
 
2 3 F e b 2 0 2 0 
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A p p r o v e d  
1 . 0
v


St atisti c al  A n al ysis  Pl a n  v 2. 1 
C A 2 0 9 4 0 1 
B M S- 9 3 6 5 5 8 
Ni v ol u m a b 
 
2 8 
A P P E N DI X  1    
S E L E C T  A D V E R S E  E V E N T S  D E FI NI TI O N  A N D  C O N V E N TI O N S 
T h e s el e ct  A d v ers e  E v e nts (s el e ct  A Es)  c o nsist  of  a list  of  pr ef err e d t er ms  gr o u p e d  b y s p e cifi c 
c at e g or y  ( e. g.   p ul m o n ar y   e v e nts,   g astr oi nt esti n a l   e v e nts   c at e g ori es)   a n d   b y  s u b c at e g or y  ( e. g.  
t h yr oi d   dis or d ers,   di a b et es,   pit uit ar y,   a dr e n al  dis or d ers  s u b c at e g ori es).   T h es e   c at e g ori es   a n d  
s u b c at e g ori es  ar e  d efi n e d  b y t h e  S p o ns or  a n d t h e list  t h at is  m ost  c urr e nt  at t h e ti m e  of  a n al ysis 
will  b e  us e d.   Als o,  c h a n g es  m a y  b e  m a d e t o  t his list  wit h  e a c h  n e w  v ersi o n  of  M e d D R A. 
F or i nf or m ati o n, t h e s el e ct  a d v ers e  e v e nts  d efi n e d  at t h e ti m e  of fi n ali z ati o n  of t h e first  v ersi o n 
of t h e  d o c u m e nt  ar e list e d i n  T a bl e  A- 2  usi n g  M e d D R A  v ersi o n  2 0. 1.   T h e fi n al list  us e d f or t h e 
cli ni c al st u d y r e p ort  will  b e i n cl u d e d i n  a n  A p p e n di x  of t h e  C S R. 
Ti m e-t o  o ns et  d efi niti o n 
Ti m e-t o   o ns et   of  s el e ct   A E  ( a n y   gr a d e)  f or   a  s p e cifi c   c at e g or y  (i. e.   p ul m o n ar y   e v e nts,  
g astr oi nt esti n al   e v e nts,  ...)  is   d efi n e d   as  t h e   ti m e   b et w e e n  t h e   d a y   of  t h e  first   d os e   of  st u d y  
tr e at m e nt  a n d t h e  o ns et  d at e  of t h e  e arli est s el e ct  A E ( of  a n y  gr a d e) i n t his  c at e g or y. 
If t h e s u bj e ct  di d  n ot  e x p eri e n c e  a s el e ct  A E ( of a n y  gr a d e) i n t h e  c at e g or y, ti m e-t o  o ns et  will  b e 
c e ns or e d  at t h e  m a xi m u m f oll o w- u p ti m e  of  all s u bj e c ts i n t h eir r es p e cti v e tr e at m e nt  gr o u p (i. e 
f or s u bj e cts  wit h o ut  a n  e v e nt, f oll o w- u p ti m e is d efi n e d fr o m first  d osi n g  d at e  u p t o l ast  d osi n g 
d at e  + 3 0  d a ys ( or  1 0 0  d a ys  d e p e n di n g  o n t h e  a n al ys is) if s u bj e cts  ar e  off tr e at m e nt  a n d f oll o w e d 
f or  at l e ast   3 0  d a ys ( or  1 0 0  d a ys  d e p e n di n g  o n t he  a n al ysis) ,  ot h er wis e it is  d efi n e d  u p t o t h e l ast 
k n o w n   ali v e   d at e).   T h e  r es ulti n g   K a pl a n- M ei er   pl ot   will  r e pr es e nt  t h e   c u m ul ati v e  r at e   of  t h e  
s el e ct  A E ( a n y  gr a d e) i n t h e  c at e g or y  o v er ti m e. 
Ti m e-t o  o ns et  of s el e ct  A E ( gr a d e  3- 5) f or  a s p e cifi c   c at e g or y is  d efi n e d simil arl y  b ut r estri ct e d 
t o  gr a d e  3- 5 s el e ct  A Es. 
Ti m e-t o   o ns et   of   dr u g-r el at e d  ( gr a d e   3- 5   or   a n y   gr a d e)  s el e ct   A E  f or   a  s p e cifi c   c at e g or y  is  
d efi n e d si mil arl y  b ut r estri ct e d  t o  dr u g-r el at e d s el e ct  A Es. 
Ti m e-t o   o ns et  f or   a  s p e cifi c  s u b c at e g or y  is   d efi n e d  si mil arl y   b ut  r estri ct e d  t o   e v e nt   of  t his  
s u b c at e g or y.  
Ti m e-t o  r es ol uti o n  d efi niti o n 
I n  or d er t o  d eri v e t h e ti m e-t o r es ol uti o n,  o v erla p pi n g  or  c o nti g u o us s el e ct  A Es  wit hi n  a s p e cifi c 
c at e g or y ( d efi n e d i n  T a bl e  A- 2 )  will  b e  c oll a ps e d i nt o  w h at  will  b e t er m e d  “ cl ust er e d ” s el e ct 
A Es.  F or  e x a m pl e, if  a s u bj e ct ( wit h o ut  pr e-tr e at m e nt  A E)  e x p eri e n c e d  a n  A E fr o m  1st t o  5t h 
J a n u ar y,  a n ot h er  A E ( wit h  diff er e nt  P T  b ut  wit hi n s a m e  c at e g or y) fr o m  6t h t o  1 1t h J a n u ar y  a n d 
s a m e  A E fr o m  1 0t h t o  1 2t h J a n u ar y, t h es e  will  b e  c oll a ps e d i nt o  o n e  cl ust er e d s el e ct  A E fr o m  1st 
t o  1 2t h J a n u ar y.  T a bl e  A- 1 is s um m ari zi n g  k e y  d eri v ati o n st e ps f or   e a c h t y p e  of  cl ust er e d s el e ct 
A Es. 
Ti m e-t o r es ol uti o n  of s el e ct  A E ( a n y  gr a d e) f or  a s p e cifi c  c at e g or y is  d efi n e d  as t h e l o n g est ti m e 
fr o m  o ns et t o  c o m pl et e r es ol uti o n  or i m pr o v e m e nt t o t h e  gr a d e  at  b as eli n e  a m o n g  all  cl ust er e d 
s el e ct   A Es  i n  t his   c at e g or y   e x p eri e n c e d   b y  t h e  s u bj e ct.   E v e nts   w hi c h   w ors e n e d  i nt o   gr a d e   5  
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e v e nts ( d e at h)  or  h a v e  a r es ol uti o n  d at e  e q u al t o t h e  d at e  of  d e at h  ar e  c o nsi d er e d  u nr es ol v e d. If  a 
cl ust er e d s el e ct  A E is  c o nsi d er e d  as  u nr es ol v e d,  t h e r es ol uti o n  d at e  will  b e  c e ns or e d t o t h e l ast 
k n o w n  d at e  ali v e. I m pr o v e m e nt t o t h e  gr a d e  at  b as eli n e i m pli es t h at  all  diff er e nt  A E  e v e nts i n t h e 
cl ust er e d s el e ct  a d v ers e  e v e nt s h o ul d  at l e ast  h a v e i m pr o v e d t o t h e  c orr es p o n di n g (i. e.  wit h s a m e 
pr ef err e d t er m)  b as eli n e   gr a d e.  T his  m e as ur e is   d efi n e d  o nl y f or s u bj e cts  w h o  e x p eri e n c e d  at 
l e ast  o n e s el e ct  A E i n t h e s p e cifi c  c at e g or y. 
T h e ti m e-t o r es ol uti o n  of s el e ct  A E ( gr a d e  3- 5) f or  a s p e cifi c  c at e g or y is  d efi n e d si mil arl y  wit h 
a n  o ns et  d at e  c orr es p o n di n g t o  a  gr a d e  3- 5 s el e ct  A E. 
Ti m e-t o r es ol uti o n  of  dr u g-r el at e d s el e ct  A E ( a n y  gr a d e  or  gr a d e  3- 5) is  d efi n e d si mil arl y  b ut 
r estri ct e d t o  dr u g-r el at e d s el e ct  A E. 
T h e ti m e-t o r es ol uti o n  of s el e ct  A E ( a n y  gr a d e  or  gr a d e  3- 5,  dr u g-r el at e d  or  all)  w h er e i m m u n e 
m o d ul ati n g  m e di c ati o n  w as i niti at e d is  d efi n e d  si mil arl y  wit h t h e  a d diti o n al  c o n diti o n t h at t h e 
s u bj e ct st art e d  a n i m m u n e  m o d ul ati n g  m e di c ati o n  d uri n g t h e l o n g est s el e ct  A E r es ol uti o n  p eri o d. 
Ti m e-t o r es ol uti o n f or  a s p e cifi c s u b c at e g or y is  d e fi n e d si mil arl y  b ut r estri ct e d t o  e v e nt  of t his 
s u b c at e g or y.  
T a bl e  A- 1:    
D e ri v ati o n  of  cl ust e r e d s el e ct  A E 
T y p e  of  cl ust e r e d s el e ct  A E 
D e ri v ati o n 
A n y  gr a d e 
C oll a ps e  a n y  o n-tr e at m e nt s el e ct  A E fr o m t h e s a m e 
c at e g or y 
 
Dr u g-r el at e d  of  a n y  gr a d e 
C oll a ps e  a n y  o n-tr e at m e nt  dr u g-r el at e d 
s el e ct  A E fr o m t h e s a m e  c at e g or y 
 
Gr a d e  3- 5 
C oll a ps e  a n y  o n-tr e at m e nt s el e ct  A E fr o m t h e s a m e 
c at e g or y. 
R es ol uti o n  will  b e  b as e d  o n t h e  o ns et  d at e  of t h e  e arli est 
gr a d e  3- 5 r e c or ds (if  n o  gr a d e  3- 5  r e c or d,  cl ust er e d s el e ct 
A E is  e x cl u d e d) 
Dr u g-r el at e d  of  Gr a d e  3- 5 
C oll a ps e  a n y  o n-tr e at m e nt  dr u g-r el at e d s el e ct  A E fr o m t h e 
s a m e  c at e g or y 
R es ol uti o n  will  b e  b as e d  o n t h e  o ns et  d at e  of t h e  e arli est 
gr a d e  3- 5 r e c or d (if  n o  Gr a d e  3- 5 r e c or d,  cl ust er e d s el e ct 
A E is  e x cl u d e d) 
 
 
T h e  al g orit h m f or  c oll a psi n g s el e ct  a d v ers e  e v e n t r e c or ds is  usi n g t h e f oll o wi n g  c o n v e nti o ns: 
F or   e a c h  s u bj e ct   a n d  s p e cifi e d   c at e g or y,  t h e   c orr es p o n di n g   a d v ers e   e v e nt  r e c or ds   will   b e  
c oll a ps e d  w h e n: 
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1)   M ulti pl e  a d v ers e  e v e nt r e c or ds   h a v e t h e s a m e  o ns et  d at e. 
2)   T h e  o ns et  d at e  of  a n  e v e nt r e c or d is  eit h er  t h e s a m e  d a y  or  1  d a y l at er t h a n t h e r es ol uti o n 
d at e  of  a  pr e c e di n g  e v e nt r e c or d ( c o nti g u o us  e v e nts). 
3)   T h e  o ns et  d at e  of  a n  e v e nt r e c or d is  aft er t h e  o ns et  d at e  a n d  pri or t o  or  o n t h e r es ol uti o n 
d at e  of  a  pr e c e di n g  e v e nt r e c or d ( o v erl a p pi n g  e v e nts). 
 
 
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T a bl e  A- 2:   
S el e ct  A d v e rs e  E v e nts  
 
C at e g o r y 
S u b c at e g o r y 
P r ef e r r e d  T e r ms 
E N D O C RI N E  A D V E R S E  E V E N T 
 
A D R E N A L  DI S O R D E R 
 
A D R E N A L I N S U F FI CI E N C Y 
A D R E N A L  S U P P R E S SI O N 
A D R E N O C O R TI C A L I N S U F FI CI E N C Y  A C U T E 
B L O O D  C O R TI C O T R O P HI N  D E C R E A S E D 
B L O O D  C O R TI C O T R O P HI N I N C R E A S E D 
H Y P O T H A L A MI C  PI T UI T A R Y  A D R E N A L  A XI S  S U P P R E S SI O N 
P RI M A R Y  A D R E N A L I N S U F FI CI E N C Y 
S E C O N D A R Y  A D R E N O C O R TI C A L I N S U F FI CI E N C Y 
 
 
DI A B E T E S 
 
DI A B E T E S  M E L LI T U S 
DI A B E TI C  K E T O A CI D O SI S 
F U L MI N A N T  T Y P E  1  DI A B E T E S  M E L LI T U S 
L A T E N T  A U T OI M M U N E  DI A B E T E S I N  A D U L T S 
T Y P E  1  DI A B E T E S  M E L LI T U S 
 
 
PI T UI T A R Y  DI S O R D E R 
 
H Y P O P H Y SI TI S 
H Y P O PI T UI T A RI S M 
L Y M P H O C Y TI C  H Y P O P H Y SI TI S 
 
 
T H Y R OI D  DI S O R D E R 
 
A T R O P HI C  T H Y R OI DI TI S 
A U T OI M M U N E  H Y P O T H Y R OI DI S M 
A U T OI M M U N E  T H Y R OI DI TI S 
B A S E D O W' S  DI S E A S E 
B L O O D  T H Y R OI D  S TI M U L A TI N G  H O R M O N E  D E C R E A S E D 
B L O O D  T H Y R OI D  S TI M U L A TI N G  H O R M O N E I N C R E A S E D 
H Y P E R T H Y R OI DI S M 
H Y P O T H Y R OI DI S M 
P RI M A R Y  H Y P E R T H Y R OI DI S M 
P RI M A R Y  H Y P O T H Y R OI DI S M 
SI L E N T  T H Y R OI DI TI S 
T H Y R OI D  F U N C TI O N  T E S T  A B N O R M A L 
T H Y R OI D  H O R M O N E S  D E C R E A S E D 
T H Y R OI D  H O R M O N E S I N C R E A S E D 
T H Y R OI DI TI S 
T H Y R OI DI TI S  A C U T E 
T H Y R O XI N E  D E C R E A S E D 
T H Y R O XI N E  F R E E  D E C R E A S E D 
T H Y R O XI N E  F R E E I N C R E A S E D 
T H Y R O XI N E I N C R E A S E D 
T RI-I O D O T H Y R O NI N E  U P T A K E I N C R E A S E D 
 
G A S T R OI N T E S TI N A L  A D V E R S E 
E V E N T 
 
A U T OI M M U N E  C O LI TI S 
C O LI TI S 
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T a bl e  A- 2:   
S el e ct  A d v e rs e  E v e nts  
 
C at e g o r y 
S u b c at e g o r y 
P r ef e r r e d  T e r ms 
 
C O LI TI S  U L C E R A TI V E 
DI A R R H O E A 
E N T E RI TI S 
E N T E R O C O LI TI S 
F R E Q U E N T  B O W E L  M O V E M E N T S 
G A S T R OI N T E S TI N A L  P E R F O R A TI O N 
L O W E R  G A S T R OI N T E S TI N A L  P E R F O R A TI O N 
U P P E R  G A S T R OI N T E S TI N A L  P E R F O R A TI O N 
 
H E P A TI C  A D V E R S E  E V E N T 
 
 
A C U T E  H E P A TI C  F AI L U R E 
A C U T E  O N  C H R O NI C  LI V E R  F AI L U R E 
A L A NI N E  A MI N O T R A N S F E R A S E I N C R E A S E D 
A S P A R T A T E  A MI N O T R A N S F E R A S E I N C R E A S E D 
A U T OI M M U N E  H E P A TI TI S 
BI LI R U BI N  C O N J U G A T E D I N C R E A S E D 
B L O O D  A L K A LI N E  P H O S P H A T A S E I N C R E A S E D 
B L O O D  BI LI R U BI N I N C R E A S E D 
D R U G-I N D U C E D  LI V E R I N J U R Y 
G A M M A- G L U T A M Y L T R A N S F E R A S E I N C R E A S E D 
H E P A TI C  E N Z Y M E I N C R E A S E D 
H E P A TI C  F AI L U R E 
H E P A TI TI S 
H E P A TI TI S  A C U T E 
H E P A T O T O XI CI T Y 
H Y P E R BI LI R U BI N A E MI A 
LI V E R  DI S O R D E R 
LI V E R  F U N C TI O N  T E S T  A B N O R M A L 
LI V E R  F U N C TI O N  T E S T I N C R E A S E D 
LI V E R I N J U R Y 
T R A N S A MI N A S E S I N C R E A S E D 
 
H Y P E R S E N SI TI VI T Y/I N F U SI O N 
R E A C TI O N  
 
 
A N A P H Y L A C TI C  R E A C TI O N 
A N A P H Y L A C TI C  S H O C K 
B R O N C H O S P A S M 
H Y P E R S E N SI TI VI T Y 
I N F U SI O N  R E L A T E D  R E A C TI O N 
 
P U L M O N A R Y  A D V E R S E  E V E N T 
 
 
A C U T E  R E S PI R A T O R Y  DI S T R E S S  S Y N D R O M E 
A C U T E  R E S PI R A T O R Y  F AI L U R E 
I DI O P A T HI C I N T E R S TI TI A L  P N E U M O NI A 
I N T E R S TI TI A L  L U N G  DI S E A S E 
L U N G I N FI L T R A TI O N 
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T a bl e  A- 2:   
S el e ct  A d v e rs e  E v e nts  
 
C at e g o r y 
S u b c at e g o r y 
P r ef e r r e d  T e r ms 
P N E U M O NI TI S 
 
R E N A L  A D V E R S E  E V E N T 
 
 
A C U T E  KI D N E Y I N J U R Y 
A U T OI M M U N E  N E P H RI TI S 
B L O O D  C R E A TI NI N E I N C R E A S E D 
B L O O D  U R E A I N C R E A S E D 
C R E A TI NI N E  R E N A L  C L E A R A N C E  D E C R E A S E D 
H Y P E R C R E A TI NI N A E MI A 
N E P H RI TI S 
N E P H RI TI S  A L L E R GI C 
P A R A N E O P L A S TI C  G L O M E R U L O N E P H RI TI S 
R E N A L  F AI L U R E 
R E N A L  T U B U L A R  N E C R O SI S 
T U B U L OI N T E R S TI TI A L  N E P H RI TI S 
U RI N E  O U T P U T  D E C R E A S E D 
 
S KI N  A D V E R S E  E V E N T 
 
 
A U T OI M M U N E  D E R M A TI TI S 
B LI S T E R 
D E R M A TI TI S 
D E R M A TI TI S  A L L E R GI C 
D E R M A TI TI S  E X F O LI A TI V E 
D R U G  E R U P TI O N 
E C Z E M A 
E R Y T H E M A 
E R Y T H E M A  M U L TI F O R M E 
E X F O LI A TI V E  R A S H 
FI X E D  D R U G  E R U P TI O N 
N O D U L A R  R A S H 
P A L M A R- P L A N T A R  E R Y T H R O D Y S A E S T H E SI A  S Y N D R O M E 
P E M P HI G OI D 
P H O T O S E N SI TI VI T Y  R E A C TI O N 
P R U RI T U S 
P R U RI T U S  A L L E R GI C 
P R U RI T U S  G E N E R A LI S E D 
P S O RI A SI S 
R A S H 
R A S H  E R Y T H E M A T O U S 
R A S H  G E N E R A LI S E D 
R A S H  M A C U L A R 
R A S H  M A C U L O- P A P U L A R 
R A S H  M O R BI L LI F O R M 
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T a bl e  A- 2:   
S el e ct  A d v e rs e  E v e nts  
 
C at e g o r y 
S u b c at e g o r y 
P r ef e r r e d  T e r ms 
R A S H  P A P U L A R 
R A S H  P R U RI TI C 
R A S H  V E SI C U L A R 
S KI N  E X F O LI A TI O N 
S KI N  H Y P O PI G M E N T A TI O N 
S KI N I R RI T A TI O N 
S T E V E N S- J O H N S O N  S Y N D R O M E 
T O XI C  E PI D E R M A L  N E C R O L Y SI S 
T O XI C  S KI N  E R U P TI O N 
U R TI C A RI A 
VI TI LI G O 
 
S o ur c e:  M e d D R A  v ersi o n  2 0. 1 
 
 
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