A Multi-Center Phase 2 Open-Label Study to Evaluate Safety and Efficacy in Subjects With Melanoma Metastatic to the Brain Treated With Nivolumab in Combination With Ipilimumab Followed by Nivolumab Monotherapy
Phase: PHASE2
Conditions: Melanoma
Sponsor: Bristol-Myers Squibb



Clinical Protocol
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2
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must 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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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 03
Section Number & 
Title
Description of Change
•
Section 5.4.3 
Confirmation of 
Scans
equivocal. 
•
Section 5.1, Flow 
Chart/ Time and 
Events Schedule, 
Table 5.1-2 On-
study Assessments 
Cycles 1 and 2 
(CA209204)
•
Section 5.1, Flow 
Chart/ Time and 
Events Schedule, 
Table 5.1-3 On-
study Assessments 
Cycles 1 and 2 
(CA209204)
•
A note in the table header
now specifies that tumor 
assessments are to be 
conducted per protocol 
even if a dose is delayed. 
The footnote regarding dose 
delay and study 
assessments has been
removed.
•
Section 5.1, Flow 
Chart/ Time and 
Events Schedule, 
Table 5.1-1
Screening 
Assessments
(CA209204)
•
Section 5.1, Flow 
Chart/ Time and 
Events Schedule, 
Table 5.1-1 On-
study Assessments 
Cycles 1 and 2 
(CA209204)
•
Section 5.1, Flow 
Chart/ Time and 
Events Schedule, 
Table 5.1-3 On-
study Assessments 
Cycle 3 and Beyond
(CA209204)
•
Section 5.1, Flow 
Chart/ Time and 
Events Schedule, 
Table 5.1-4 Follow-
up Assessments
(CA209204)
•
Presentation of Tumor 
Assessment aligned to 
program-wide standards. No 
content change.
•
Section 5.4 Efficacy 
Assessments
•
Revised to align with 
Schedule of Activities.  No 
content change. 
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 03
Section Number & 
Title
Description of Change
• Section 8.5.9, 
Interim Analyses
•
Revised based on results of 
interim analyses.
Appendix 3: Image 
Assessment Criteria
1.1: Measurability of 
tumor
Required thickness of MRI scan 
slice for intracranial lesions 
≤10 mm LD and >10 mm LD 
are now specified in second 
bullet.
Throughout the 
document.
Minor editorial or formatting 
changes/corrections
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BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1) Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood. 
2) Allow time necessary for subject or subject's legally acceptable representative to inquire about 
the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject's legally 
acceptable representative and by the person who conducted the informed consent discussion. 
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
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 
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.
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INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is an open-label, multi-site Phase 2 study of nivolumab combined with ipilimumab followed 
by nivolumab monotherapy for the treatment of subjects with melanoma metastatic to the brain. 
Per Amendment 02 (August 2106), both asymptomatic and symptomatic patients are eligible for 
enrollment as described below:
Cohort A (asymptomatic) Patients with histologically confirmed metastatic melanoma 
presenting with intracranial metastases and at least 1 measurable index intracranial metastasis 
≥0.5 cm and ≤3 cm in diameter that has not been previously irradiated. No clinical requirement 
for local intervention (surgery, radiosurgery, corticosteroid therapy) or other systemic therapy.  
Approximate enrollment in Cohort A is 90 patients.
Cohort B (symptomatic): Patients with histologically confirmed metastatic melanoma presenting 
with symptomatic intracranial metastases who may be on steroids with doses no higher than a total 
daily dose of 4 mg of dexamethasone or equivalent that is stable or tapering within 10 days prior 
to treatment. Patients who are symptomatic and are not being treated with steroids are also eligible. 
Patients enrolled in Cohort B must have at least 1 measurable index intracranial metastasis 
≥0.5 cm and ≤3 cm in diameter that has not been previously irradiated, must not require 
immediate local therapy (SRT or surgery within 3 weeks prior to first treatment), have a 
performance status 0-2, and no experience of seizure within 10 days prior to first treatment.
Approximate enrollment in Cohort B is 20 patients.
Asymptomatic subject who are enrolling into Cohort A and become symptomatic during the 
screening evaluations may be considered for enrollment into Cohort B if they meet all other criteria 
for Cohort B. No crossover between cohorts is permitted after the start of treatment.
Subjects who have received prior treatment with BRAF inhibitors and/or MEK inhibitors, and 
subjects who have been treated with ipilimumab in an adjuvant setting are eligible for the study.
All patients will be treated with the combination regimen of nivolumab 1 mg/kg combined with 
ipilimumab 3 mg/kg Q3W (4 doses), followed by nivolumab monotherapy (3 mg/kg Q2W) for a 
maximum of 24 months, or until disease progression or unacceptable toxicity. The use of SRT
(single episode) for disease progression for ≤ 3 intracranial lesions is permitted. (Section 3.4.2.2)
Recommended intervals between treatment with study drug and use of SRT, dose delay after SRT, 
allowable steroid use (≤ 16 mg dexamethasone PO QD), and tapered over no more than 4 weeks),
and observation of patients post SRT when treatment is resumed are also specified in Section
3.4.2.2. Any subject who meets criteria for discontinuation following SRT (Section 4.5.5) will 
proceed to follow-up for safety, progression, and overall survival after discontinuation of study 
medication based on the assessment schedules presented in Section 5. NOTE: To continue on-
study after SRT, at least 1 non-irradiated target lesion must remain after SRT treatment.
A follow-up period of 3 years from the date of first treatment with study drugs is available for all 
subjects. The study will close after the last enrolled subject completes 3 years of follow up from 
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the date of first treatment or the study is discontinued by the Sponsor. The study design is presented
in Figure 3.1-1:
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Additional imaging may be performed for patient care at the discretion of the investigator. All 
efficacy objectives will be based on Investigator assessment at the study site. 
All radiologic imaging from this study will be transmitted to a centralized imaging core laboratory 
for storage and analysis. Sites will be informed of quality issues or the need for repeat scanning 
via queries from the core lab. The details of the independent review performed by the Independent 
Radiologic Review Committee (IRRC) are outlined in a separate CA209204 Imaging Review 
Charter.
Safety will be evaluated for all treated subjects using the NCI CTCAE version 4.0. Safety 
assessments will be based on medical review of AE reports, vital sign measurement results, 
physical examinations, and clinical laboratory tests. In addition, a designated Steering Committee
composed of a core group of study investigators who are experts in treating patients with 
melanoma intracranial metastases and sponsor physicians/staff will evaluate safety and efficacy 
throughout the trial as described in Section 7.
 
 
Safety and Tolerability Assessment Evaluation of Risk/Benefit 
An interim analysis was conducted when 20 subjects completed induction or discontinued 
treatment for any reason. At the completion of the interim analysis by the steering committee, the 
combination was determined to be safe in patients with asymptomatic untreated melanoma 
intracranial metastases. Per Amendment 02 (August 2016), the patient population will be expanded 
to include Cohort B, which will enroll approximately 20 patients with symptomatic intracranial
metastases who may be on steroids provided there is no immediate need for SRT or surgery (within 
3 weeks prior to first treatment, performance status is 0-2, the patient has not experienced seizure 
within 10 days prior to first treatment, and does not require steroid therapy at a total daily dose of 
higher than 4 mg of dexamethasone or equivalent, which is stable or tapering for 10 days prior to 
first treatment. Patients who are symptomatic and are not being treated with steroids for CNS 
symptoms are eligible for enrollment.
In the event unfavorable safety/tolerability event occurs in the interim analyses, the Steering 
Committee and the Sponsor will review the available data. Upon review of the risk/benefit profile,
the Sponsor and the Steering Committee will recommend continuation, modification, or 
termination of the study. 
The most frequent severe drug related AEs for the combination of nivolumab and ipilimumab in 
melanoma have been asymptomatic and reversible (eg, laboratory testing of liver function tests 
(LFT) and lipase levels) and preliminary evidence shows deep and durable responses in advanced 
melanoma (CA209004) despite these events. In particular, any assessment of the risk/benefit will 
be examined if the following criteria are met:
•
A majority of subjects have at least stable disease or a partial tumor response
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•
All treatment-related AEs leading to discontinuation are non-fatal, reversible, and without 
severe sequelae 
•
A majority of the treatment related AEs are laboratory in nature, asymptomatic, and 
monitorable by routine blood draws.
If a decision is made to continue because of a favorable risk/benefit profile (ie, non-fatal AEs in 
subjects with at least stable disease or a partial tumor response) and despite meeting the safety 
signals for ‘not tolerable’ criteria, the EC/IRBs must be notified, Informed Consent forms updated 
if necessary to add new information, and discussion of the risk/benefit, if determined to be different 
than at the outset of the study, must be documented with all current and future subjects who are 
enrolled into the study. 
3.1.1
Screening Phase
•
Screening begins by establishing the subject’s initial eligibility and signing of the ICF.
•
Subject is enrolled using the IRT. Subjects will be enrolled into either Cohort A 
(asymptomatic) or Cohort B (symptomatic). Asymptomatic subjects who are enrolling into 
Cohort A and become symptomatic during the screening evaluations may be considered for 
enrollment into Cohort B if they meet all other criteria for Cohort B. No crossover between 
cohorts is permitted after the start of treatment.
•
Subject is assessed for study eligibility as described in Section 3.3.1 and Section 3.3.2.
•
Pre-treatment tumor tissue is required from all patients and should be from an excisional, 
incisional, (preferred), punch, or core needle biopsy. Tissue representing an extracranial 
metastasis collected after prior therapies is preferred, but archival primary or metastatic tumor 
tissue specimens are acceptable. A tumor tissue block or minimum of 15 slides should be 
submitted.
3.1.2
Treatment Phase
•
A negative pregnancy test should be documented within 24 hours prior to start of each dose of 
investigational product.
•
On study laboratory assessments should be drawn within 72 hours prior to dosing.
•
Study assessments are to be collected as outlined in Table 5.1-2 (Cycles 1 and 2) and 
Table 5.1-3 (Cycles 3 and beyond). 
•
Adverse event assessments should be documented at each clinic visit. 
•
Outcomes Research Assessment (Healthcare Resources Utilization (HCRU) will be conducted 
prior to Cycle 1 dosing and at the time of progression.
•
Exploratory Biomarker Testing will be conducted according to Table 5.6.1.3-1.
•
All enrolled participants will be treated with nivolumab IV over 60 minutes ± 10 minutes at 1 
mg/kg combined with ipilimumab administered IV over 90 minutes ± 10 minutes at 3 mg/kg 
every 3 weeks for a total of 4 doses of the combination therapy followed by nivolumab 
administered IV over 60 minutes ± 10 minutes at 3mg/kg every 2 weeks for a maximum of 24 
months or until progression or unacceptable toxicity.
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•
Study drug dose may be delayed for toxicity. Tumor assessment should be continued
as per protocol even if dosing is delayed.
•
Response to treatment will be evaluated by serial radiographic assessment every 6 weeks 
(± 7 days) for the first 12 months and every 12 weeks (± 7 days) thereafter until documented 
progression.
•
NANO Scale evaluation to be conducted weekly during Cycle 1, prior to dosing on Weeks 1 
and 4 in Cycle 1 and Cycle 2; and on Weeks 1, 3, and 5 during Cycle 3 and thereafter during 
the treatment phase. See Section 8.4.3.1.
•
The treatment phase ends when the subject is discontinued from study therapy. For a complete 
list of reasons for treatment discontinuation see Section 3.5.
3.1.3
Follow-Up Phase
•
Begins when the decision to discontinue a subject from treatment is made (no further treatment 
with study therapy).
•
After completion of the first two follow-up visits, subjects will be followed every 3 months for 
survival.
•
Follow-up assessments are to be collected as outlined in Table 5.1-4.
•
Subjects who discontinue treatment for reasons other than tumor progression will continue to 
have tumor assessments beginning 6 weeks (± 7 days) from the first dose of study drug for the 
first 12 months, and every 12 weeks (± 7 days) thereafter until documented tumor progression.
•
Subjects will be followed for drug-related toxicities until these toxicities resolve, return to 
baseline or are deemed irreversible. All adverse events will be documented for a minimum of 
100 days after last dose.
3.2
Post Study Access to Study Drug
At the end of the study, BMS will not continue to provide BMS supplied study drug to 
subjects/investigators unless BMS chooses to extend the study. The investigator should ensure that 
the subject receives appropriate care to treat the condition under study. Subjects who continue to 
respond at the end of on study treatment may be prescribed study medication through commercial 
supply.
3.3
Study Population.
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed consent form 
in accordance with regulatory and institutional guidelines. This must be obtained before 
the performance of any protocol-related procedures that are not part of normal subject care.
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory testing, and other requirements of the study.
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2. Target Population
a) Histologically confirmed  malignant melanoma with measurable metastases in the brain
b) Cohort A: At least 1 measurable intracranial metastasis > 0.5 cm and < 3 cm in longest 
diameter that has not been previously irradiated. No clinical requirement for local 
intervention (surgery, radiosurgery, corticosteroid therapy) or other systemic therapy. 
Cohort B: Per Amendment 02 (August 2016) Subjects with neurologic signs and 
symptoms related to metastatic intracranial lesions are eligible per Amendment 02.
Subjects must have at least 1 measurable intracranial metastasis ≥0.5 cm and ≤3 cm in 
longest diameter that has not been previously irradiated. No immediate requirement 
(within 3 weeks prior to first treatment) for local intervention (surgery, radiosurgery, 
corticosteroid therapy). Steroid use is permitted as defined in inclusion criterion 2e).
c) Prior stereotactic radiotherapy (SRT) and prior excision of up to 3 melanoma intracranial
metastases is permitted if there has been complete recovery, with no neurologic sequelae,
and measurable lesions remain. 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. Any prior SRT to intracranial lesions or prior excision must have 
occurred ≥3 weeks before the start of dosing for this study.
d) Must have tumor tissue available for biomarker analysis. Biopsy should be excisional, 
incisional, punch, or core needle. Fine needle aspirates or other cytology samples are not 
allowable.
e) Cohort A (asymptomatic): Subjects must be free of neurologic signs and symptoms 
related to metastatic intracranial lesions and must not have required or received systemic 
corticosteroid therapy within 10 days prior to first treatment. 
Cohort B (symptomatic): Subjects with neurologic signs and symptoms related to 
metastatic intracranial lesions are eligible per Amendment 02. Subjects with neurologic 
signs and symptoms may be treated with a total daily dose of no more than 4 mg of 
dexamethasone that is stable or tapering for 10 days prior to first treatment. Subjects with 
neurologic signs and symptoms who are not being treated with steroids are eligible for 
Cohort B. No experience of seizure within 10 days prior to first treatment.
f)
Allowable prior therapy
i)
Approved adjuvant therapies, which may include molecularly-targeted agents, 
IFN-α, and ipilimumab. Patients who received ipilimumab as adjuvant therapy must 
have a 6 month washout before receiving any dosing on this study
ii) For advanced disease, interleukin-2 at any dose and/or IFN-α (any formulation, no 
washout required); MEK and BRAF inhibitors: washout for at least 4 weeks prior to 
the start of dosing in this study
iii) Steroids for physiological replacement are allowed.
g) Cohort A (asymptomatic): ECOG performance status ≤ 1.
Cohort B: (symptomatic):  ECOG performance status ≤ 2
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h) Screening laboratory values must meet the following criteria (using CTCAE v4):
•
WBC
≥2000/uL
•
Neutrophils
≥1500/uL
•
ANC
≥1000/uL
•
Platelets 
≥100 x 103/uL
•
Hemoglobin 
≥9 g/dL 
•
Serum Creatinine 
≤1.5 x ULN or calculated creatinine clearance > 40 mL/min 
(using the Cockcroft-Gault formula)
Female CrCl = (140- age in years) x weight in kg x 0.85
72 x serum creatinine in mg/ dL
Male CrCl = (140- age in years) x weight in kg x 1.00
72 x serum creatinine in mg/ dL
•
AST
≤3.0 x ULN 
•
ALT
≤3.0 x ULN
•
Total Bilirubin 
≤1.5 x ULN, (except subjects with Gilbert’s syndrome who must 
have a total bilirubin < 3.0 x ULN).
i)
Subject Re-enrollment:  This study permits the re-enrollment of a subject who has 
discontinued the study as a pre-treatment failure (ie, has not been treated) if the reason for 
pre-treatment failure is related to the size of potential index lesions. If re-enrolled, the 
subject must be re-consented.
3. Age and Reproductive Status
a) Males and Females, ≥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) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception for a period of 30 days (duration of ovulatory cycle) plus the 
time required for the investigational drug to undergo approximately five half lives. 
WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus 
the time required for nivolumab to undergo five half-lives) after the last dose of 
investigational drug.
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the 
time required for the investigational drug to undergo approximately five half lives. 
Males who receive nivolumab who are sexually active with WOCBP must continue 
contraception for 31 weeks (90 days plus the time required for nivolumab to undergo five 
half-lives) after the last dose of investigational drug.
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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.
At a minimum, subjects must agree to the use of two methods of contraception, with one method 
being highly effective and the other method being either highly effective or less effective as listed 
below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
•
Male condoms with spermicide
•
Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, 
injectables, implants and intrauterine devices (IUDs) such as Mirena® by WOCBP subject or 
male subject’s WOCBP partner. Female partners of male subjects participating in the study 
may use hormone based contraceptives as one of the acceptable methods of contraception since 
they will not be receiving study drug
•
Nonhormonal IUDs, such as ParaGard®
•
Tubal ligation 
•
Vasectomy.
•
Sexual Abstinence
−
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.
−
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence.
LESS EFFECTIVE METHODS OF CONTRACEPTION
•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal sponge
•
Male Condom without spermicide 
•
Progestin only pills by WOCBP subject or male subject’s WOCBP partner 
•
Female Condom*.
* A male and female condom must not be used together
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3.3.2
Exclusion Criteria
1) Target Disease Exceptions
a) History of known leptomeningeal involvement (lumbar puncture not required).
b) Previous stereotactic or highly conformal radiotherapy within 3 weeks before the start of 
dosing for this study. Note the stereotactic radiotherapy field must not have included the 
intracranial index lesion(s). 
c) Subjects previously treated with SRT > 3 lesions in the brain
d) Intracranial lesion size > 3cm 
2) Medical History and Concurrent Diseases
a) History of whole brain irradiation.
b) Subjects with an active, known or suspected autoimmune disease. Subjects with type I 
diabetes mellitis, 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.
c) Subjects with major medical, neurologic or psychiatric condition who are judged as unable 
to fully comply with study therapy or assessments should not be enrolled. 
d) Any concurrent malignancy other than non-melanoma skin cancer or carcinoma in situ of 
the cervix.  For any prior invasive malignancy, at least 5 years must have elapsed since 
curative therapy and patients must have no residual sequelae of prior therapy.
e) Cohort A: (asymptomatic): The use of corticosteroids is not allowed within 10 days prior 
to first treatment (based upon 5 times the expected half-life of dexamethasone) except 
patients who are taking steroids for physiological replacement. If alternative 
corticosteroid therapy has been used, consultation with the sponsor Medical Monitor is 
required to determine the washout period prior to initiating study treatment.
Cohort B: (symptomatic): Subjects with neurologic sign and symptoms related to 
intracranial metastases who are being treated with a total daily dose of higher than 4 mg 
dexamethasone or equivalent within 10 prior to the start of treatment with study drug are 
excluded.
f)
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg 
daily prednisone equivalent, are permitted in the absence of active autoimmune disease. 
g) Subjects with history of life-threatening toxicity related to prior ipilimumab adjuvant 
therapy except those that are unlikely to re-occur with standard countermeasures (eg. 
hormone replacement after adrenal crisis).
3) Physical and Laboratory Test Findings 
g) Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic 
infection
h) Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS) even if fully immunocompetent on ART—
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All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5. The only exception to this requirement is when a subject 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study 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 case report form (CRF) page.
3.6
Post Study Drug Study Follow up
In this study, clinical benefit rate is the primary 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.
BMS may request that survival data be collected on all treated subjects outside of the protocol 
defined window (Table 5.1-4). At the time of this request, each subject will be contacted to 
determine their survival status unless the subject has withdrawn consent for all contacts or is lost 
to follow-up.
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-retained 
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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 (Table 4-1):
•
All products, active or placebo, being tested or used as a comparator in a clinical trial. 
•
Study required premedication, and 
•
Other drugs administered as part of the study that are critical to claims of efficacy 
(eg, background therapy, rescue medications)
•
Diagnostic agents: (such as glucose for glucose challenge) given as part of the protocol 
requirements must also be included in the dosing data collection.
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Table 4-1:
Study Drugs for CA209204
Product Description / 
Class and Dosage 
Form
Potency
IP/Non-IMP
Blinded or Open Label
Packaging/ Appearance
Storage Conditions
(per label)
Nivolumab Solution 
for Injection
100 mg 
(10 mg/mL)
IP
Open-label
Clear to opalescent colorless 
to pale yellow liquid. May 
contain particles
2 to 8° C. 
Protect from light, freezing and 
shaking.
Ipilimumab Solution 
for Injection
200 mg 
(5 mg/mL)
IP
Open-label
Clear, colorless to pale 
yellow liquid. May contain 
particles
2 to 8° C. 
Protect from light and freezing.
Premedications or medications used to treat infusion-related reactions should be sourced by the investigative sites if available and permitted by local regulations.
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational products are nivolumab and ipilimumab.
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products. 
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be dispensed 
and contact BMS immediately.
Investigational product documentation (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).
Infusion-related supplies (eg IV bags, in-line filters, 0.9% NaCl solution) will not be supplied by 
the sponsor and should be purchased locally if permitted by local regulations. 
For non-investigational product, if marketed product is utilized, it should be stored in accordance 
with the package insert, summary of product characteristics (SmPC), or similar. 
Please refer to the current version of the nivolumab and ipilimumab IBs and/or pharmacy reference 
sheets for complete storage, handling, dispensing, and infusion information for BMS-936558 
(nivolumab) and BMS-734016 (ipilimumab).
Nivolumab 
Nivolumab vials must be stored at a temperature of 2° C to 8° C and should be protected from 
light, freezing, and shaking. If stored in a glass front refrigerator, vials should be stored in the 
carton. Recommended safety measures for preparation and handling of nivolumab include 
laboratory coats and gloves.
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For details on prepared drug storage and use time of nivolumab under room temperature/light and 
refrigeration, please refer to the nivolumab IB section for “Recommended Storage and Use 
Conditions” and/or pharmacy reference sheets. Care must be taken to assure sterility of the 
prepared solution as the product does not contain any anti-microbial preservative or bacteriostatic 
agent. No incompatibilities between nivolumab and polyolefin bags have been observed.
Nivolumab is to be administered as a 60-minute IV infusion ± 10 minutes using a volumetric pump 
with a 0.2/0.22 micron in-line filter at the protocol-specified dose. The drug can be diluted with 
0.9% normal saline for delivery but the total drug concentration of the solution cannot be below 
0.35 mg/ml. It is not to be administered as an IV push or bolus injection. At the end of the infusion, 
flush the line with a sufficient quantity of normal saline.
Ipilimumab
Ipilimumab injection can be used for IV administration without dilution after transferring to a PVC 
(polyvinyl chloride), non-PVC/non-DEHP (di-(2-ethylhexyl)phthalate) or glass containers and is 
stable for 24 hours at 2-8ºC or room temperature/room light (RT/RL). For ipilimumab storage 
instructions, refer to ipilimumab IB and/or pharmacy reference sheets. Recommended safety 
measures for preparation and handling include protective clothing, gloves, and safety cabinets. 
Ipilimumab is to be administered as a 90-minute IV infusion ± 10 minutes, using a volumetric 
pump with a 0.2 to 1.2 micron in-line filter at the protocol-specified dose. The drug can be diluted 
with 0.9% normal saline or 5% Dextrose Injection to concentrations between 1 mg/mL and 4 
mg/mL. It is not to be administered as an IV push or bolus injection. Care must be taken to assure 
sterility of the prepared solutions, since the drug product does not contain any antimicrobial 
preservatives or bacteriostatic agents.
When both study drugs are to be administered on the same day, separate infusion bags and filters 
must be used for each infusion. Nivolumab is to be administered first. The nivolumab infusion 
must be promptly followed by a saline flush to clear the line of nivolumab before starting the 
ipilimumab infusion.
4.4
Method of Assigning Subject Identification
CA209204 study is an open-label study. 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
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4.5
Selection and Timing of Dose for Each Subject.
All enrolled subjects will be treated in an open-label fashion as described below:  
•
Nivolumab administered IV over 60 minutes ± 10 minutes at 1 mg/kg combined with 
ipilimumab administered IV over 90 minutes ± 10 minutes at 3 mg/kg every 3 weeks for a total 
of 4 doses of the combination therapy followed by nivolumab administered IV over 60 minutes
± 10 minutes at 3mg/kg every 2 weeks for a maximum of 24 months or until progression or 
unacceptable toxicity.
Dosing schedule is detailed in Table 4.5-1 and Table 4.5-2 .
.
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Table 4.5-1:
CA209204: Dosing Schedule for Cycle 1 and Cycle 2
1 Cycle = 6 weeks
Day 1
Week 1
Day 1
Week 2
Day 1
Week 3
Day 1
Week 4
Day 1
Week 5
Day 1
Week 6
All Enrolled Subjects
Combination Treatment (Nivolumab 
1mg/kg + Ipilimumab 3 mg/kg) 
1 mg/kg 
Nivolumab +
3 mg/kg 
Ipilimumab 
1 mg/kg 
Nivolumab +
3 mg/kg 
Ipilimumab
Table 4.5-2:
CA209204 Dosing Schedule Cycle 3 and Beyond 
Subjects may continue to receive treatment for a maximum of 24 months from the Date of the First Treament with Nivolumab +Ipilimumab.  
1 Cycle = 6 weeks
Day 1
Week 1
Day 1
Week 2
Day 1
Week 3
Day 1
Week 4
Day 1
Week 5
Day 1
Week 6
All Enrolled Subjects
Nivolumab monotherapy
3 mg/kg 
Nivolumab
3 mg/kg 
Nivolumab
3 mg/kg 
Nivolumab
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•
Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for reasons 
other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in the presence 
of Grade 2 AST/ALT OR total bilirubin
•
Subjects with combined Grade 2 AST/ALT AND
total bilirubin values meeting 
discontinuation parameters (Section 4.5.5) should have treatment permanently discontinued.
•
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Subjects with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by the BMS Medical Monitor.
•
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with the BMS Medical Monitor
Dose delay of treatment that results in treatment interruption of > 6 weeks requires treatment 
discontinuation, with exceptions as noted in Section 4.5.2.1 and Section 4.5.5  
There will be no dose reductions for study medications.
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 next scheduled time point will be delayed until dosing resumes.
•
If treatment is delayed > 6 weeks, the subject must be permanently discontinued from study 
therapy, except as specified in Section 4.5.2.1 and Section 4.5.5.
4.5.5
Discontinuation of Study Drug
Treatment should be permanently discontinued for the following:
•
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment 
•
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, 
hypersensitivity reactions, infusion reactions, and endocrinopathies::
−
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity reaction, or 
infusion reaction of any duration requires discontinuation
−
Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation
−
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except: 
♦Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
•
Any drug-related liver function test (LFT) abnormality that meets the following criteria require 
discontinuation: 
−
AST or ALT > 8 x ULN
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−
Total bilirubin > 5 x ULN
−
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
•
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events which do not require discontinuation:
−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia
−
Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis. The BMS Medical Monitor should be consulted for 
Grade 4 amylase or lipase abnormalities.
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
•
Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events 
are allowed. Prior to re-initiating treatment in a subject with a dosing delay lasting > 6 
weeks from the previous dose, the BMS medical monitor must be consulted. Tumor 
assessments should continue as per protocol even if dosing is delayed. Periodic study visits 
to assess safety and laboratory studies should also continue every 6 weeks or more 
frequently if clinically indicated during such dosing delays.
−
Dosing delays lasting > 6 weeks from the previous dose 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 delay lasting > 6 weeks, the BMS medical monitor 
must be consulted. Tumor assessments should continue as per protocol even if dosing is 
delayed. Periodic study visits to assess safety and laboratory studies should also continue 
every 6 weeks or more frequently if clinically indicated during such dosing delays.
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued nivolumab or 
ipilimumab dosing.
Note: If a subject experiences a severe adverse event during induction treatment (ie, the 
combination of nivolumab and ipilimumab) that requires discontinuation from further treatment
with the combination, continuing treatment with nivolumab monotherapy may be considered
contingent on discussion with and approval by the BMS Medical Monitor.  
Exceptions to Permanent Discontinuation of study drug dosing under the following situations:
•
Potentially reversible inflammation (< Grade 4), attributable to a local anti-tumor reaction and 
a potential therapeutic response. This includes inflammatory reactions at sites of tumor 
resections or in draining lymph nodes, or at sites suspicious for, but not diagnostic of 
metastasis.
•
Subjects with the following conditions where in the investigator’s opinion continuing study 
drug administration is justified:
−
Endocrinopathies where clinical symptoms are controlled with appropriate hormone 
replacement therapy.
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including description of reasonably foreseeable risks or discomforts, or other alternative treatment 
options will still apply
For subjects who continue study therapy beyond progression, further progression is defined as an 
additional 10% increase in tumor burden volume from time of initial PD. This includes an increase 
in the sum of diameters of all target lesions and/or the diameters of new measurable lesions 
compared to the time of initial PD. Treatment with study medication should be discontinued 
permanently upon documentation of further 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. 
Arrangements for the return of study drug will be made by the responsible Study Monitor.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Assessments (CA209204)
Procedure
Screening
Visit
Notes
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening.  
Medical History
X
Tumor Tissue Samples
X
•
Pre-treatment tumor tissue is required from all patients and should be from an excisional, 
incisional, (preferred), punch, or core needle biopsy. Tissue representing an extracranial metastasis 
collected after prior therapies is preferred, but archival primary or metastatic tumor tissue 
specimens are acceptable.  A tumor tissue block or minimum of 15 slides should be submitted.
•
The following are optional:
-H&E of primary cutaneous melanoma with accompanying pathology report; where available but 
strongly recommended (can be submitted at later date)
-Intracranial metastasis: Any biopsy specimen acceptable (block or minimum of 15 slides); where 
available 
•
-Submit a copy of the original pathology reports that correspond to submitted specimens if 
available.
Safety Assessments
Complete Physical Examination
X
Vital Signs and oxygen saturation
X
Including BP, HR, temperature, and oxygen saturation by pulse oximetry. Pulse oximetry at rest and 
after exertion. Obtain vital signs at the screening visit and within 72 hours prior to first dose
Physical Measurements 
X
Height and weight
Performance Status
X
ECOG
X
Within 14 days prior to dosing
Assessment of Signs and Symptoms
X
Within 14 days prior to dosing
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Table 5.1-1:
Screening Assessments (CA209204)
Procedure
Screening
Visit
Notes
Laboratory Tests
X
CBC w/differential, Chemistry panel including: LDH, AST, ALT, ALP, T.Bili, BUN or serum urea 
level, creatinine, Ca, Mg, Na, K, Cl, Glucose, amylase, lipase, TSH, Free T4, Free T3, Hep B/C (HBV 
sAG, HCV antibody, or HCV RNA) within 14 days prior to dosing
Pregnancy Test (WOCBP Only) 
X
Serum or urine must be performed.
Efficacy Assessments 
Tumor Assessment
X
Section 5.4
CT/MRI Chest, abdomen, pelvis and all known or suspected sites of disease within the prior 28 days.
Brain MRI is required within the prior 14 days.
Scans must follow sponsor-supplied Imaging Manual.
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Table 5.1-3:
On-study Assessments Cycle 3 and Beyond (CA209204) 
Procedure
Cycle 3 and Beyond (Cycle = 6 weeks)
Notes
•
Tumor assessment should be continued
as per protocol even if dosing is delayed.
•
Subjects may continue to receive 
treatment for a maximum of 24 months 
from the Date of the First Treatment with 
Nivolumab +Ipilimumab.
Day 1
Week 1
Day 1
Week 2
Day 1
Week 3
Day 1
Week 4
Day 1
Week 5
Day 1
Week 6
Administer Study Treatment 
Nivolumab 3 mg/kg
X
X
X
Dose will remain the same as long as current 
patient weight is within 10% of the Cycle 1/Day 
1/enrollment weight 
Doses may be administered within 2 days after 
the scheduled date if necessary. 
Subjects may continue to receive treatment for a 
maximum of 24 months from the Date of the First 
Treatment with Nivolumab +Ipilimumab
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Table 5.1-4:
Follow-up Assessments (CA209204)
Procedure
Follow-Upa
Visits 1 and 2
Survivalb
Follow-up Visits
Notes
Follow up is 3 years from start of treatment.
Efficacy Assessments
Tumor Assessments
X
Only for subjects who have not progressed on study therapy or who have 
discontinued study treatment for reasons other than documented disease 
progression.
Section 5.4
CT/MRI of chest, abdomen, pelvis and brain (MRI)
FIRST tumor assessment should first be performed at 6 weeks (± 7 days) 
from first dose date.
SUBSEQUENT tumor assessments should occur every 6 weeks (± 7 
days) up to first 12 months (week 48), then every 12 weeks (±7 days) until 
documented disease progression.
a Follow-up Visit 1 = 30 days from the last dose +/- 7 days or coincide with the date of discontinuation (+/- 7 days) if date of discontinuation is greater than 37 
days after last dose, Follow-up visit 2 = 84 days (+/- 7 days) from follow-up visit 1
b Survival visits = every 3 months from Follow-up Visit 2 +/- 7 days
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5.1.1
Retesting During Screening or Lead-in Period 
Retesting of laboratory parameters and/or other assessments during the Screening or Lead-in 
period will not be permitted (this does not include parameters that require a confirmatory result) 
unless there was a technical error in performance of the lab test and the first result is invalid.
Any new result will override the previous result (ie, the most current result prior to dosing) and is 
the value by which study inclusion will be assessed, as it represents the subject’s most current, 
clinical state.
5.2
Study Materials
•
NCI CTCAE version 4.0
•
Nivolumab Investigator Brochure
•
Ipilimumab Investigator Brochure
•
Pharmacy Binder
•
Laboratory manuals for collection and handling of blood (including biomarker) and tissue 
specimens
•
Site manual for operation of interactive voice response system, including enrollment 
worksheets
•
Pregnancy Surveillance Forms
•
RECIST 1.1 pocket guide
•
CA209204 Imaging Manual
5.3
Safety Assessments
5.3.1
Medical History, Physical Exam, Physical Measurements 
At baseline, a medical history will be obtained to capture relevant underlying conditions. The 
baseline examinations should include weight, height, ECOG Performance Status, blood pressure 
(BP), heart rate (HR), temperature, and oxygen saturation by pulse oximetry at rest (also monitor 
amount of supplemental oxygen if applicable) should be performed within 28 days prior to first 
dose. 
Baseline local laboratory assessments should be done within 14 day prior to first dose and are to 
include: CBC w/differential, Chemistry panel including: LDH, AST, ALT, ALP, T.Bili, BUN or 
serum urea level, creatinine, Ca, Mg, Na, K, Cl, Glucose, amylase, lipase, TSH, Free T4, Free T3, 
Hep B/C (HBV sAG, HCV antibody, or HCV RNA).
While on-study and during follow-up, local laboratory assessments are to be conducted as 
specified on Table 5.1-2 to Table 5.1-4. Thyroid function testing is to be done every 6 weeks (every 
3 cycles) for subjects receiving nivolumab.
Subjects will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be continuous during the treatment phase. During study treatment and nivolumab Follow-Up 
Visits 1 and 2, toxicity assessments should be done in person. Once subjects reach the survival 
follow-up, either in-person visits or documented telephone calls/email correspondence to assess 
the subject’s status are acceptable.
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Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.0.
Oxygen saturation by pulse oximetry at rest (also monitor amount of supplemental oxygen if 
applicable) should be assessed at each on-study visit prior to dosing. The start and stop time of the 
study therapy infusions should be documented. 
Physical examinations are to be performed as specified in Section 5.1 and as clinically indicated. 
If there are any new or worsening clinically significant changes since the last exam, report changes 
on the appropriate non-serious or serious adverse event page.
On treatment local laboratory assessments are to be completed within 72 hours prior to dosing.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme evaluations) will be monitored during the follow-up phase via on site/local 
labs until all study drug related toxicities resolve, return to baseline, or are deemed irreversible.
If a subject shows changes on pulse oximetry or other pulmonary-related signs (hypoxia, fever) or 
symptoms (eg. dyspnea, cough, fever) consistent with possible pulmonary-related signs (hypoxia, 
fever) or symptoms (eg, dyspnea, cough, fever) consistent with possible pulmonary adverse events, 
the subject should be immediately evaluated to rule out pulmonary toxicity, according to the 
suspected pulmonary toxicity management algorithm in the BMS-936558 (nivolumab) IB.
Some of the assessments referred to in this section may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
5.3.2
Vital Signs
Vital signs consist of blood pressure, heart rate, respiratory rate and temperature measurements. 
Vital signs will be obtained as outlined in Table 5.1-1 to Table 5.1-3. 
5.3.3
Imaging Assessment for the Study
All subjects will undergo CT scanning and volumetric MRI of the brain at the time points specified 
in Table 5.1-1 to Table 5.1-4.
CT and MRI scans will be assessed locally per the modified RECIST 1.1 criteria outlined in 
Appendix 3. Up to 5 extracranial and 5 intracranial lesions will be followed for efficacy per the 
criteria. Please refer to Appendix 3 for guidelines regarding images, target lesion selection and 
response criteria.
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.
Clinically significant radiologic findings or changes from baseline scans will be coded as adverse 
events or serious adverse events according to the criteria described in Section 6.
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5.3.4
Pregnancy Testing
WOCBP are required to have several pregnancy tests performed as presented in Table 5.1-1 to 
Table 5.1-4. A negative serum or urine pregnancy test must be documented at the screening visit
as per Table 5.1-1. Additionally WOCBP must exhibit 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; therefore the screening pregnancy test may need to be repeated prior to the start of 
study drug dosing. A serum or urine pregnancy test will also be conducted at End of Treatment 
Visit.
5.3.5
ECOG Status
ECOG performance status will be evaluated at the screening evaluation and at each visit as outlined 
in Time and E. An outline of the ECOG performance status is provided in Appendix 2.
5.3.6
Adverse Event Monitoring
Adverse Events (AEs) will be evaluated according to the NCI CTCAE Version 4.0 on a continuous 
basis starting from when the subject takes the first dose of study administration, up to and including 
Follow-Up and End of Treatment visits (at minimum, for 100 days following last dose of study 
drug). Serious Adverse Events (SAEs) must be collected from the time period following written 
consent to participate in the study up to and including follow-up.
5.3.7
Laboratory Test Assessments
Results of all safety laboratory collections must be obtained and reviewed in advance of study drug 
dosing, as applicable. Amylase and lipase should be collected with the chemistry collection, but 
these lab results do not require review prior to dosing. 
Serum Chemistry is to be obtained as specified in Table 5.1-1 to Table 5.1-4. A free-T4 and free-T3 
will be performed reflexively for out of range TSH values. A CBC with differential is to be 
obtained. The CBC with differential includes hemoglobin, hematocrit, white blood cells, platelets 
(direct platelet count), erythrocyte sedimentation rate, WBC differential enumeration of total and 
percentage of neutrophils, lymphocytes, eosinophils, basophils and monocytes.
5.4
Efficacy Assessments 
Assessment of extracranial disease (by CT scan or other approved modalities and intracranial
disease (by MRI scan) will be performed per the schedule in Table 5.1-1 to Table 5.1-4. 
Investigators may obtain more frequent follow-up MRI scans as medically indicated. 
Baseline assessments should be performed within 28 days prior to first dose of study drug utilizing 
CT or MRI for systemic lesions and within 14 days for brain lesions (MRI only). In addition to 
chest, abdomen, pelvis, and brain, all known sites of disease should be assessed at baseline. 
Subsequent assessments should include chest, abdomen, pelvis, brain, and all known sites of 
disease and should use the same imaging method as was used at baseline. Subjects will be 
evaluated for tumor response beginning at 6 weeks (± 7 days) from the first dose of study drugs 
for the first 12 months and every 12 weeks (± 7 days) thereafter, until disease progression is 
documented or treatment is discontinued (whichever occurs later). Tumor assessments for ongoing 
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study treatment decisions will be completed by the investigator using RECIST (Response 
Evaluation Criteria in Solid Tumors) 1.1 criteria for all systemic lesions and modified RECIST 1.1 
for brain lesions (Appendix 3).
Radiographic images will be collected and sent to a centralized imaging core laboratory for storage 
and potential future central reading.
All radiologic imaging from this study will be assessed at the study site by the Investigator. Sites 
will be trained in image acquisition parameters, image analyses, and submission process, prior to 
scanning the first study subject. These guidelines will be outlined in a separate CA209204 Site 
Imaging Manual. 
For extracranial disease assessment, contrast-enhanced computed tomography (CT) scans acquired 
on dedicated CT equipment is preferred for this study. CT with contrast of the chest, abdomen and 
pelvis and other areas of disease are to be performed for tumor assessments per Table 5.1-1 to 
Table 5.1-4. Should a subject have a contraindication for CT IV contrast, a non-contrast CT of the 
chest and a contrast enhanced MRI of the abdomen and pelvis may be obtained. MRI’s should be 
acquired with slice thickness of < 5 mm with no gap (contiguous). 
Use of CT component of a PET/CT scanner: Combined modality scanning such as with FDG-
PET/CT is increasingly used in clinical care, and is a modality/technology that is in rapid 
evolution; therefore, the recommendations outlined here may change rather quickly with time. At 
present, low dose or attenuation correction CT portions of a combined FDG-PET/CT are of limited 
use in anatomically based efficacy assessments and it is therefore suggested that they should not 
be substituted for dedicated diagnostic contrast enhanced CT scans for anatomically based 
RECIST measurements. However, if a site can document that the CT performed as part of a FDG-
PET/CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast) then the 
CT portion of the FDG-PET/CT can be used for RECIST 1.1 measurements. Note, however, that 
the FDG-PET portion of the CT introduces additional data which may bias an investigator if it is 
not routinely or serially performed.
MRI scans: Bi-dimensional and three-dimensional contrast enhanced MRI of the brain will be 
acquired per the CA209204 Imaging Manual requirements. Every attempt should be made to 
image each subject using an identical acquisition protocol on the same scanner for all imaging time 
points. Cases of suspected radiologic disease progression will be confirmed by an MRI performed 
approximately 4 weeks after the initial radiological assessment of progression.
5.4.1
Computed Tomography Imaging (CT)
Baseline CT assessments should be performed within 28 days prior to enrollment. In addition to 
chest, abdomen, pelvis, all known sites of disease should be assessed at baseline. 
Subsequent CT assessments should occur at +/- 7 days per scheduled visits and should include 
chest, abdomen, and pelvis, and all known sites of disease.  The same imaging method used at 
baseline should be used for all CT assessments. Subjects will be evaluated for tumor response 
every 6 weeks for Year 1 and every 12 weeks thereafter until progression or discontinuation, 
whichever is later.
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5.4.2
Brain Magnetic Resonance Imaging (MRI)
All subjects will receive efficacy assessments with brain MRI at time points specified in Table 
5.1-1 to Table 5.1-4.  Baseline brain MRI should be performed with 14 days prior to enrollment.
All MRIs should occur at ± 7 days per scheduled visits. Investigators may obtain more frequent 
follow-up MRI scans as medically indicated.
5.4.3
Confirmation of Scans
Verification of Response: Confirmation of intracranial response will be confirmed by an MRI 
performed approximately 4 weeks after the initial radiological assessment. If repeat scans confirm 
overall response (OR), then response should be declared using the date of the initial scan. If repeat 
scans do not confirm OR, then the subject is considered not to have had an OR. 
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal and will be confirmed by an MRI performed approximately 4 weeks after the initial 
radiological assessment of progression. If repeat scans confirm PD, then progression should be 
declared using the date of the initial scan. If repeat scans do not confirm PD, then the subject is 
considered not to have progressive disease.
5.4.4
Algorithms for Response Assessments
5.4.4.1
Primary Efficacy Assessment
The primary endpoint of the study is intracranial CBR > 6 months in subjects with malignant 
melanoma with intracranial metastases treated with nivolumab combined with ipilimumab 
therapy. Tumor response will be based on Investigator assessment using modified RECIST 1.1.
5.4.4.2
Secondary Efficacy Assessments
The secondary efficacy endpoints include extracranial CBR > 6 months using RECIST 1.1 and 
will be based on Investigator assessment.
Additional secondary endpoints are specified in Section 8.4.2.
 
 
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•
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).
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 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 
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must be collected that occur during the screening period and within 100 days of discontinuation of 
dosing.
The investigator should report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
An SAE report should be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS (or 
designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on a 
Pregnancy Surveillance Form (electronic or paper forms). 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:
SAE Email Address: Worldwide.Safety@BMS.com
SAE Facsimile Number:  See Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. When paper forms are used, the 
original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report. 
All SAEs should be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects. 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
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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:
•
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 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 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
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 
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.
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Cohort A will enroll asymptomatic subjects (n ~ 90), and Cohort B will enroll symptomatic
subjects (defined in Section 3.3.1).
Table 8.1-1 presents the clinical benefit rates (CBRs) that would have to be observed to yield 
clinically meaningful results with respect to the lower bounds of the Clopper-Pearson exact 
two sided 90% and 95% CI. The planned sample size ensures that the maximum width of the exact 
90% CI for any given CBR estimate does not exceed 18% and the maximum width of the exact 
95% CI for any given CBR estimate does not exceed 20%.
Table 8.1-1:
CA209204: Clinical Benefit Rates – two sided 90% confidence 
interval (Clopper-Pearson)
Nivolumab + Ipilimumab
(n=110) 
Clinically 
meaningful CBR
Observed CBR 
Clopper-Pearson 
exact two-side 90% 
CI 
Clopper-Pearson exact 
two-side 95% CI 
Brain 
(intracranial)
40%
53/110 (48.2%) 
57/110 (51.8%)
(40.0%, 56.4%)
(43.6%, 60.0%)
(38.5%, 57.9%)
(42.1%, 61.5%)
Systemic
(extracranial)/
Global
(intracranial
+extracranial)
50%
65/110 (59.1%)
(50.8%, 67.0%)
(49.3%, 68.4%)
CBR = Clinical Benefit Rate
If the observed intracranial CBR rate is 51.8%, the sample size of 110 will achieve 80.4% power 
to detect a difference of 11.8% (51.8% versus 40% historical intracranial CBR rate) with a type I 
error rate of 0.10 for the two-sided binomial test.  
8.2
Populations for Analysis
•
All Enrolled Subjects: All subjects who signed an informed consent form and were registered 
into the IVRS
•
All Treated Subjects: All subjects who received at least one dose of any study medication. 
  
8.3
Endpoint  Definitions
8.3.1
Tumor Assessment Endpoints
8.3.1.1
Best Overall Response (BOR) per Subject 
The best overall response is determined once all the data for the subject is known. It is defined as 
the best response designation, as determined by the investigator, recorded between the date of first 
dose of study drug and the date of objectively documented progression or the date of subsequent 
therapy, whichever occurs first. For subjects without documented progression or subsequent 
therapy, all available response designations will contribute to the BOR assessment.
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In this study, BOR is specified for the intracranial, extracranial, and global compartments based 
on the (1) modified RECIST 1.1 criteria (intracranial), (2) RECIST 1.1 criteria (extracranial), (3) 
combination of modified RECIST 1.1 criteria and RECIST 1.1 criteria (global). Image assessment 
criteria (modified RECIST 1.1 and RECIST 1.1) are presented in Appendix 3.
For the assessment of BOR, all available assessments per subject are considered. 
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules, listed in order of priority:
•
CR = At least two determinations of CR at least 4 weeks apart before progression.
•
PR = At least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR).
•
SD = At least one SD assessment ≥6 months after start of treatment.
•
PD = At least two determinations of PD at least 4 weeks apart after start of treatment (and 
not qualifying for CR, PR or SD).
The BOR for each patient will also be determined by the IRRC as specified within the CA209204 
Imaging Review Charter.
8.3.1.2
Overall Survival
Overall Survival (OS) is defined as the time from the date of the start of treatment until the date of 
death. For those subjects who have not died, OS will be censored at the recorded last date of subject 
contact, and subjects with a missing recorded last date of contact will be censored at the last date 
the subject was known to be alive.
8.4
Endpoints
8.4.1
Primary Endpoint
Intracranial clinical benefit rate (CBR) defined as the proportion of patients, whose best overall 
response according to modified RECIST1.1, is either complete response (CR), a partial response 
(PR) or stable disease (SD).
The primary endpoint is intracranial CBR. It is defined as the proportion of all treated subjects 
whose best overall response is either a CR or PR or whose best overall response was SD with 
duration of >6 months, as determined by modified RECIST 1.1 criteria for index intracranial
lesions based on investigator review.  
8.4.2
Secondary Endpoint(s)
Secondary endpoints are as follows: 
•
Intracranial ORR and intracranial PFS per modified RECIST 1.1 criteria; 
•
Extracranial CBR, extracranial ORR, extracranial PFS per RECIST 1.1 criteria
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Global (intracranial + extracranial) CBR, global ORR, and global PFS per a combination 
of modified RECIST 1.1 criteria for intracranial lesions and RECIST 1.1 for extracranial
disease
•
OS
•
Safety and tolerability will be measured by the incidence of AE adverse events, serious 
adverse events (SAE), deaths, and laboratory abnormalities.
Overall survival (OS) is defined as the time from first dosing date to the date of death, will be 
estimated using the Kaplan-Meier product-limit method, with subjects censored at their last known 
date alive.  
Progression-free survival (PFS) is defined as the time between the date of first dose of study drug
and the first date of documented confirmed progression, as determined by the investigator, or death 
due to any cause, whichever occurs first. Subjects who die without a reported progression will be 
considered to have progressed on the date of their death. Subjects who did not progress or die will 
be censored on the date of their last evaluable tumor assessment. Subjects who did not have any 
on study tumor assessments and did not die will be censored on the date of first dose of study drug. 
Subjects who started anti-cancer therapy without a prior reported progression will be censored on 
the date of their last evaluable tumor assessment prior to the initiation of subsequent anti-cancer 
therapy.
Overall response rate (ORR) is defined as the number of subjects who achieve a best overall 
response of complete response (CR) or partial response (PR) divided by the number of treated 
subjects. The best overall response is defined as the best response designation recorded between 
the date of first study dosing date and the date of progression, or the date of subsequent anticancer 
therapy (including tumor-directed radiotherapy and tumor-directed surgery), whichever occurs 
first.
Safety and tolerability will be measured by the incidence of adverse events, serious adverse events, 
deaths, and laboratory abnormalities.
 
 
 
 
 
 
 
  
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version 4.0 (CTCAE v4). Additionally, serious adverse events (SAE) will be reported from the 
time of consent forward for all subjects. The analysis of safety will be based on the frequency of 
AEs and their severity for all treated subjects. Worst toxicity grades per subject will be used in the 
summary for AEs and laboratory measurements by using the CTCAE v4. 
Safety analyses will be summarized in all treated subjects by subgroup (prior to study with or 
without SRT and on study with or without SRT) and for the overall population.  All treatment 
emergent AEs, drug-related AEs, SAEs and drug-related SAEs will be tabulated using worst grade 
per NCI CTCAE by system organ class and preferred term. On-study lab parameters including 
hematology, chemistry, liver function and renal function will be summarized using worst grade 
per NCI CTCAE criteria.
 
 
 
 
 
 
8.5.9
Interim Analyses
To assess safety and tolerability, an interim analysis was conducted after 20 subjects completed 
induction treatment or discontinued treatment for any reason. At the completion of the interim 
analysis by the steering committee, the study drug treatment was deemed safe in asymptomatic 
patients. Per Amendment 02 (August 2016), the patient population was expanded to include Cohort 
B which will enroll approximately 20 symptomatic patients as specified in Section 3.3.1.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be 
submitted to:
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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
BMS representatives will review data centrally to identify potential issues to determine a schedule 
of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents.
In addition, the study may be evaluated by BMS internal auditors and government inspectors who 
must be allowed access to CRFs, source documents, other study files, and study facilities. BMS 
audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to BMS. 
9.1.2.1
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. 
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9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and procedure, 
electronic CRFs, 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): ipilimumab. Records or logs must comply with 
applicable regulations and guidelines and should include:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number 
•
amount dispensed to and returned by each subject, including unique subject identifiers
•
amount transferred to another area/site for dispensing or storage
•
nonstudy disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for bioavailability/bioequivalence, if applicable 
•
dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
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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.
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.
The data collected during this study are confidential and proprietary to BMS. Any publications or 
abstracts arising from this study require approval by BMS prior to publication or presentation and 
must adhere to BMS’s publication requirements as set forth in the approved clinical trial agreement 
(CTA). All draft publications, including abstracts or detailed summaries of any proposed 
presentations, must be submitted to BMS at the earliest practicable time for review, but at any 
event not less than 30 days before submission or presentation unless otherwise set forth in the 
CTA. BMS shall have the right to delete any confidential or proprietary information contained in 
any proposed presentation or abstract and may delay publication for up to 60 days for purposes of 
filing a patent application.
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10
GLOSSARY OF TERMS
Term
Definition
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 (eg, 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
AI
accumulation index
AI_AUC
AUC Accumulation Index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Cmax
Cmax Accumulation Index; ratio of Cmax at steady state to Cmax after 
the first dose
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
A-V
atrioventricular
β-HCG
beta-human chorionic gonadotrophin
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
C
Celsius
C12
concentration at 12 hours
C24
concentration at 24 hours
Ca++
calcium
CBC
complete blood count
CBR
Clinical benefit ratio
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
CLcr
creatinine clearance
CLR
renal clearance
CLT
total body clearance
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Term
Definition
cm
centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CNS
Central nervous system
CRF
Case Report Form, paper or electronic
Ctrough
Trough observed plasma concentration
CV
coefficient of variation
CYP
cytochrome p-450
D/C
discontinue
dL
deciliter
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EEG
electroencephalogram
eg
exempli gratia (for example)
ESR
Expedited Safety Report
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
g
gram
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
HCO3-
bicarbonate
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
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Term
Definition
ICD
International Classification of Diseases
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
IU
International Unit
IV
intravenous
K+
potassium
kg
kilogram
L
liter
LD
longest dimension
LDH
lactate dehydrogenase
ln
natural logarithm
mg
milligram
Mg++
magnesium
MIC
minimum inhibitory concentration
min
minute
mL
milliliter
mmHg
millimeters of mercury
MS
mass spectrometry
MTD
maximum tolerated dose
μg
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
ng
nanogram
NIMP
non-investigational medicinal products 
NSAID
nonsteroidal anti-inflammatory drug
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Term
Definition
OS
Overall survival
PD
pharmacodynamics
PK
pharmacokinetics
PO
per os (by mouth route of administration)
PT
prothrombin time
PTT
partial thromboplastin time
QC
quality control
QD, qd
quaque die, once daily
RBC
red blood cell
SAE
serious adverse event
SD
standard deviation
SOP
Standard Operating Procedures
sp.
species
Subj
subject
t
temperature
T
time
TID, tid
ter in die, three times a day
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
x g
times gravity
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