A Phase II Single Arm Study of High-Dose IL-2 and Ipilimumab in Patients With Unresectable Stage III and Stage IV Melanoma
Phase: PHASE2
Conditions: Recurrent Melanoma, Stage IIIA Melanoma, Stage IIIB Melanoma, Stage IIIC Melanoma, Stage IV Melanoma
Sponsor: CINJRegulatory

Official Title:
A Phase ll Single Arm Study of High-Dose lL-2 and
lpilimumab in Patients With Unresectable Stage lll and
Stage lV Melanoma
NCT number:
02203604
Document Type:
Study Protocol and Statistical Analysis Plan; lnformed
Consent Form Main
Date of the
Document:
08 / 11. / 2ot; ; 0e I 17 / 201s

Title: A Phase II Sirrgle Anu Shrd-v of High-Dose IL-2 and Ipilinruruab in Patierrts with
Urreseclatrle Stage III aud Stage lV Nlelartotna
Princinal Iuvestigatot' :
Supported b'r':
Drus(s) [:ndet'hr
( ONrIDfr-rI",u.
Protocol Version Date: 1 1 Augtst 101 6: Version 4.{)
r
Paee I

pl.ot*col: A Plmse II Single,fu'rir Snrdl'of High-Dose IL-l ald lliilirnrurrot: il Patrents n'ith Lhuesectable
Stase I11 arrr.rl Staqe I\i r"lelauolra
Prruc$al t,r."ertigatort f
CLINICAL PROTOCOL CAl 84.084
A Phase ll Single Arm Study of High-Dose ll.z and lpilimumab in
Patients with Unresectable Stage lll and Stage lV Melanoma
Principal lnvestigator
and Coordinating Center:
Protocol Amendment 4.0 / 11 August 2416
Prntocol Ver*ion Date: I I Ausust l0l6: \'ersion: 4.0
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prol.col: .{ Phase II Single furn snrth'oiHig,lt-Dose IL-l arld lpilr,*r*rab i, Patierrts rvitli Uruesectable
Srace III artd Stase I\' \lelauorlra
I
TABLE OF CONTENTS
TABLE OF CONTENTS 
"""""""""'3
PROTOCOL SYNOPSIS.-'."..'.... 
"""""""""""'7
1 
INTRODUCTION 
""""""14
1.1 
Research Hypothesis """"""" 
"""14
1.2 
Product Development Rationale """""' 
""""15
1.2.1 
CTLA-4 and T Cell Activation 
"""'19
l.3SummaryofResultsoflnvestigationalProgram........'20
1.3.1 
Pharmacology of lpilumumab """"""" 
""""'20
1.3.2 
Pre-Clinical Toxicology of lpilumumab """"""" 
"""""'21
1.3.3 
Human Pharmacokinetics of lpilumumab """"' 
""""""21
1.3.4 Clinical Safety with lpilumumab 
"""""""""'22
1.3.4.a Details of Drug-Related Adverse Events""' 
"""""""""23
1.3.4.b Details of Drug-Related serious Adverse Events 
""""23
1.3.5 
lmmune-Related Adverse Events (irAEs) with lpilimumab """""23
1.3.5.a Drug'Related Deaths ....."""" 
"""'27
1.3.5.b Safety of 10 mglkg Multiple Doses 
"""""""'27
1.3.5.c Neuropathies -...-..-... 
""'28
1.3.6 Clinical Efficacy of lpilimumab """""" 
""""'28
1.3.6.a Relationship Between Re$ponse and lmmune Related Events in
Patients wiifr Uetastatic Melanoma 
"""""""30
1.4 
Safety of tnterleukin-2'--"" 
""""31
1.5 
Overall Risk/Benefit Assessment 
""""""""'32
1.6 
Study Rationale 
""""""33
2 
STUDY OBJECTIVES .."..'.." 
""""'3s
2.1 
Primary Objective 
""""'35
2.2 
Secondary Objectives.."""""" 
'-"'35
3 
sruDY DESIGN 
""""""37
4 
SUBJECT SELECTION CRITERIA """"""' 
""""""""""'41
4.1 
lnclusion Criteria 
"""""41
4.2 
Exclusion Criteria 
""""'43
4.3 
Data Safety Monitoring Plan 
""""'44
Prntocol \iersiort Date: I I Atre.ust ?016: \'ersion: J'0

protocol: A p'ase II sr*gle ,\ru Stud'ot Hig'-Dose IL-r a*d l,iiu,rr'ralr i, patieuts *'it'Lrruesecteble
Stace III .rrtd Stase [\' \lelanortta
I
5 
DRUG ADMINSTRATION GUIDEL|NES"""""" """""""45
lpilimumab.............. 
"""45
Storage, Preparation, and Administration """"""""""45
Preparation and Administration Guideli nes " " " """ "" "".- " " "".' "45
5.1.3 
Dose Modifications """"' 
"""""""47
5.1.3.a lpilimumab Dose Delay Rule """" 
""""""""'47
5.1.4 
Discontinuation of Study Therapy 
""""""'-"48
Permanent Discontinuation of lpilimumab """""" 
"""'49
5.1
5.1.1
5.1.2
s.1.5
5.1.5.a Permanent Discontinuation for Related Adverse Events""""""'49
5,1,5.bExceptionstoPermanentDiscontinuation...,..,.....'...,.'50
5.1.6
5.1.7
5.1.7.a
5.1.7.b
5.1.7.c
5.2
5.2.1
5.2.2
5.2.3
5.2.4
5.3
5.3.1
5.3.2
5.3.3
6
6.1
6.2
6.2.',|
6.2.2
6.2.3
6.2.3.a
lmmune-Related Adverse Events {irAEs): Definition, Monitoring,
and Treatment...'.... 
"""'50
Other Guidance 
""""""51
Treatment of lnfusion Reactions Associated with lpilimumab ""Sl
Treatment of lpilimumab-Related lsolated Drug Fever --......'.... " " 52
LiverFunctionTests(LFT}AssessmentsRequiredPriorto
Administration of lpilimumab...-....."' 
""""""53
lnterleukin-2 (lL-2; Aldesleukin; Proleukin) """"" 
""""53
Storage, Preparation, and Administration of lL-2"""""""""""""53
lL-2 Formulation/Reconstitution: lL.2 (Aldesleukin@) .........,........54
Dose Modifications of lL'2.......... 
"""""""""'54
Definitions of lL-2 Dose-Limiting Toxicity""""""' 
""""55
Prohibited and Restricted Therapies During the study...'.'......-...56
Prohibited Therapies 
""".'""""""56
Restricted Therapies 
""""""""""56
Precautions........--' 
"""'56
STUDY PROCEDURES AND OBSERVATIONS .."..".""57
Time and Events Schedule .....'......' 
"""""""57
Procedures bY Visit 
"""58
Study Procedures by Visit and Treatment Cycle 
""""59
Screening/Basetine Visit ..-....' 
"""59
Treatment Visits 
"""""60
lnduction Treatment -...-...-'..'-
I I August l016: \'ersron; 4 0

Protocol: A Phase II Si,gle A,rr Stucly of Hig,h-Dose IL'3 ad I,ilir'umab i' Patie'ts rvith uruesectable
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Protocol: A Phase 11 Silgle Anu Snrdy of Hig'lrDose IL-
Srage lll rttt{ Stage I\' \telaltolun
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Protocol Versiott Date: I I August 1016: \'erstori: { t.}
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protocol: A Plnse Ii siiigle .tu1}l Sttrcl-v of Hig,h-Dose ll-l aricl Iliilirnru'rlab in Patie[tr rvith Lhuesectable
Sraqe III artd Stase I\' \lelanorrlr
I
...89
13.0 
Human Subjects.'
13.1
13.2
13.3
13.4
13.5
13.6
14
15
Subject Population...'.-' 
"""""'89
Potential Risks. 
""""""'89
Consent Procedures......... 
""",'".''90
Potential Benefits-- 
"""""'90
Risk-Benefit Ratio-.. 
"""90
Gender and Minorities..-. 
""""""'90
Economic/Financial Considerations""" 
""".'"'90
Publication of Research Findings"""""' 
"""'91
APPENDIX 1 List of Abbreviations""' 
"""""'92
APPENDIX 2 General Approach to Toxicity Management....'...................,....93
APPENDIX 3 Management of lmmune-Related Adverse Events """""""""-94
APPEND|X 4 Management of Gl/Diarrhea Toxicity """""" 
""""""96
APPENDIX 5 Management of Hepatic Toxicity 
""""""'97
APPENDIX 6 Management of Endocrine Toxicity""""""' 
""""""'99
Subject Registration Forrn.. 
"""'100
Subject Eligibility Form'... 
"""""""101
Subject Off'Study Form 
"""""""110
ECOG Performance Status Table 
""""""""111
Tumor Measurement Sheet 
""""'112
References.............. 
""1'13
I I Augrtrst lfll6: \'ersion: 4 0

Phase ll single Arm study of High-Dose lL-2 and lpilimumab in Patients with
nresectable Stage lll and Staqe lV Melanoma
ffi 
of rpirimumab ano nrghdose rL-2 improves clinical
responses.
The combination of lpilirnumab and
acceptable safetY Profile'
high*dose lL-2 is feasible and has an
3. The combination of lpilimumab and
effector CD8+ T cells and decreased
resoondinq Patients.
high-dose lL-2 results in increased
CDa*FoxP3+ regulatory T cells in
US FDA
ients witl be enrolled as follows:
tudyDesign:lpilimumab(10mglkg)fo-r4cycles(Days1'22'43'64)andhigh-
dose ll-i for 2 cycles (Days 22-26,43-47)'
week 24, maintenance lpilimumab will be given and at 3 month intervals for 4
doses.
gth of Treatment: The total treatment period is 15 months and follow-up will
continue for a total of 36 months
dy Design lnductton: lpilimumab (10 mg/kg) for 4 doses (Days 1'22,43,64)
unO nigi-Oose lL-2 for 2 cycles (Days 22-26' 43-47)'
Maintenance lpilimumab: At week 24, maintenance lpilimumab will be given and
at 3 month intervals for 4 doses'
Term Survival Follow-up: Will be conducted by phone every 6 months'
pitinrurnaO {Yervoy)
sach patient will receive ipilimumab 10. mg/kg by intraven"yt- (]y] 'll1t-':::,"::
r",l"i"r''t."i 'b"t;; or tV push). Yervoy is approved for the treatment of
static melanoma bY the U.S. FDA
rleu kin-2 (Aldesleukin)
h patient will receive lL-2 given intravenously (lV) in a dos.e " -U^O?:???.|Y',1"1
ilH;,"ffir, i"i'rplo iq ao."r in each cycie according to institutional
idelines. Aldesleukin is approved for the treatment of metastatic melanoma by
dy Schema:
protocor: A p'ase iI si*gle .&,r st.dy of Hig,'-Dose IL-r a,d lpilir,rur,ab i, pafie,ts *'ir' Lrrueseclable
Sraee III arrd Stase I\']rlelauottta
I
PROTOCOL SYNOPSIS
Protocol Versiott Date
I I Atrgtrst l0l6: Versiorl: '1.0

protocol: A Plmse 11 Single .tulr stucly of High-Dose lIJ-l al}d Ipilirnumnb i[ Patierttr rvith Lhueseclable
Srace III atttl Slage l\' \telanorua
I
ry Endpoint:
l.Thebestoverallresponserateatorbeforeweek24oftreatmentper
rnodified WHO resPonse criteria'
ondary Clinical EndPoints:
1. SafetY and feasibilitY
2. Progression-free survival
3. Overall survival
4. Survival rate at 1, 2 and 3 Years
5. Best overall resPonse rate
6. Disease control rate (CR+PR+SD)
u*lrnJ ipitirnumaO (ig'mglkg i.v. infusion over 90 minutes)as follows:
ilimumab (10 mg/kg) for 4 cycles (Days 1' 22' 43' &\ and high-dose lL-2
(500,000 lu/kg every g nours to 14 iotal doses as tolerated) for 2 cycles
(Days 22-26.4347). 
ri--^^^
j*^i,rg on week 24, patients who do not have disease progresslon or
inu"J"ptuole toxicity will receive maintenance ipilimumab (10 mg/kg) lV over
g0 minutes. Treatment i"p"utt every 90 days for a maximum of 4 courses in
the absence of oiseaie progression or unacceptable toxicity. once
maintenance ipilimumab is completed patients will go into long term survival
follow up.
:ondary lmmune EndPoints :
1^Frequency of effector CDB+ T cells
2.Frequency of CD4+FoxP3+ regulatory T cells
trial emPloYing
andardhigh-doselt-.2(ooo'0001-Ulkgi,v.everyShoursto.l"xmaxin:um
nts will be followed for up to 36 months from study enrollment for survival
nalysis. lpilimumab will be provided by BMS.
Iitittof 82 patients will be enrolled'
0 / month with the expectation that accrual will be complete in 12 months and
will be comPlete at 48 months'
dy Design:
crual Goal:
otal number of
I Rate:
of
expected
-1A-14 - 09-10-15
10-15 - 09-10-16
ollow-Up ComPlete 09-1 0-1 I
ollow Up:
Protocr-rl Velsiort Date: I I Aug.ir>t l{Jl6: \:ersiou -1 0
I
Page 9
dd-mm-yy)

stage IlI aud stase n'lElglElll
Prrucipal Ilrvestigator
mmune studies at Screening and week 1 (baseline) and at weeks, 4 , 7,
lndl2andat6andt2months(CD8+Tcells'Tregs)
ffi?tt 
tr'e following criterta:
1) Willing and able to give written informed consent'
2) Histologic or cytJlogic diagnosis of cutaneous melanoma that is
considered unr"r""t"6ie istale lll) or metastatic (stage lV). ocular and
mucosal melanoma is excluded'
3) Required values for initial laboratory tests:
WBC
. ANC
' Platelets r 75 x 103/uL
' Hemoglobin :9 g/dL (r 80 g/L' may be transfused)
' Creatinine 12.0 x ULN
. A$T/ALT i e.s * ULN for patients without liver metastasis' a 5
times for patients with liver metastases
. Total Bilirubin I 2.0 x ULN, (except patients with Gilbert,s Syndrome,
who must have a total bilirubin less than 3'0 mgldl)
4) No known active or chronic infection with Hlv, Hepatitis B. or Hepatitis c'
Testing is not required unless clinically-suspected
5) Performance status (ECOG 0-1)'
Oi Ratients must have a life expectancy of greater than three months at the
start of the trial.
7) Patients must have a brain MRI that is free of active metastases'
Metastases that have been treated with radiation or surgical resection, are
stable for at least 4 weeks and do not require steroids are eligible'
8) Patients may have received treatment of completely resected early stage
melanoma, comprising interferon, radiation treatment, or experimental
vaccinetherapy,andinthemetastaticsettingpatientcanhavehad
treatment such as chemotherapy, immunotherapy (except prior treatment
with lpilimumab and lL-2), and other experimental agent which was
completed 4 weeks prior to enrollment'
9)Normalcardiacstresstestforpatientsover50yearsofage.
tb; eutmonary Function: FEV1 and FVC > 650/o of prediction for those
patients with extensive pulmonary metastases or chronic pulmonary
disease history.
11) Men and women, ''' 18 Years of age.
: 2000/uL
::. 1000/uL
nclusion
Protocol; A Phase II Single Arn Studl' of Hig'h-Dose IL-l ald lpilirmrma[r irr Patients u'ith Uru'esectable
Protocol Versiou Date: I I Arrgu-rt 1016l Versrr:rr: 4 0
Page

xclusion
riteria:
hoto,cor; A phase II Si*gre fu,r study of Higrr-Dose IL-3 a'd lpilir*tu,ab i, patie'rs *'ith Lhueseclable
Srage III atrd Stage tVS!39%
iil" rrrl 1,t'-.t,gu to., I
including' but no1 limited to' ongoing or
active infection, symptomatic congestivl heart failure'. y":1i?1139::i
ffiffi;, or plycfriatric illnesstsocial situations that
would limit studY comPliance
2. Any other malrgnancy form which the patient has been,disease-free for less
than 5 years, witrr.tne exception o{ adequately treated and cured basal or
squamous cett st<in cancer,'superficial biadder cancer or carcinoma in situ
of the cervix,
3.Patientswithprimaryocularormucosalmelanomaareexcluded'
4.Autoimrnunedisease:Patientswithahistoryofinflammatorybowel
disease. incruoing ulcerative colitis and Crohn's Diseasse, are excluded
from this study, "i "i" 
patients with a history of symptomatic disease (e'g''
rheumatoid arthritis, systemic progressive sclerosis [scleroderma]' systemic
lupus erythematosus' autoimmune vasculitis [eg' Wegener's
Granulomatosiuti; moioi neuropathy considered of autoimmune origin (e'g'
Guillain-Barre Syndrome and Myasthenia Gravis)'
5. Any underlying meoicat o, puycnirtric condition, which in the opinion of the
investigator wil ;;k; tne administration of ipilimumab hazardous or
obscuretheinterpretationofAEs,suchasaconditionassoctatedwith
frequent diarrhea.
6. Patients with underlying heart conditions who are deemed ineligible for
rurg".y ny caraioioqy cJnsutt. Patients with reversible ischemic changes on
cardiac stress test.
T.Anynon.oncologyvaccinetherapyusedforpreventionofinfectious
diseases (for up io t montn before oi after any dose of ipilimumab)'
8. A history of prior treatment with lL-2, ipilimumab or.prior CTLA4 inhibitor or
agonist for metastatic disease, Prior therapy with ipilimumab in the adjuvant
settingrsallowedprovidedtherewerenoGrade3orgreateradverse
events that did not iesotve with limited corticosteroid use' and more than 6
months nave etapseo since final adjuvant treatment and start of study
treatment on thrs Protocol.
9. Concomitant therapy with any of.the following. interferon' or other non-
studyimmunotherapyregimens:cytotoxicchemotherapy;
immunosuppr*iriu" ,guntr; otheiinvestigation therapies; or chronic use of
sYstemic corticosteroids.
10,women of chitdbearing potential (wocBP)' defined above in section 4'1'
an acceptable method of contraception to
study period and for at least I weeks after
b.have a positive pregnancy test at baseline' or
c.are Pregnant or breastfeeding'
11. Prisoners or subjects who are compulsorrly detained (involuntarily
incarcerated) for treatment of either a psychiatric or physical (eg, infectious)
illness.
who:
a.are unwilling or unable to use
avoid pregnancY for their entire
cessation of studY drug, or

Efficacywillbebasedonappropriate-imagingstudies(CT.scanofthe
chest, abdomen ano-fetvis and MRI of the brain) at specified time points'
PET scan will be oon* onrv for lesions that cannot be assessed by cT
imaging.
SafetywillbedeterminedbyNClCTCAE,version4.0.Criteriafor
itoppinq drug and puti"ni withdrawat due to toxicity are detailed in
Section 5.0 of the protocol. An interim safety analysis y'l-?: conducted
after the first 6 patienti are enrolled. An independent DSMB will review
ine satety data'and if concerns are found the ipilimumab dose will be
reduced to 3 mg1kg.
Standardstoppingrulesforlpilimumabwillbefollowedaccordingto
current practice guidelines, lL-2 doses will be held per standard practice
gui;fiil;r; f f--Z -wifi ne stopped for standard stopping criteria and as
detailed in Section I of the protocol'
riteria for
aluation:
Efficacy, safetY,
rnificant clinical effect we will expect ihe combination to yield a response rate of
least 28Vo based on a previous Phase I trial. ln order to have B0-o/o power at
pha=0.05 using a one sided one sample test under.. binornial distribution
;sumption to detect this difference, 82 evaluable patients will need to be
used' Continuous
ariables will be presented by summary statistics (such as i"T:.Ii.111
;tandard error and gOoZo Ct and categorical variables by frequency distributions
i.e., frequen"y .oun*, R"r""ntrg"r ind 90o/o cl). The primary endpoint will_be
e best objective response at oibefore week 24 as determined by the modilied
HO-i"tponse criteria t*WHOl. We will estimate the objectv:-1":T::"-i:',"^1:
re ratio of the numoer'or patients having best objective response over the total
umber of patients: this objective response rate will be compared with published
lie of lpilimumab alone'and lL-2 alone using exact one sample
tests.
:or sample size calculations, we assume that 14Yo of patients will respond to
pilimumab alone and 17Yo (will respond to .lL-2 tPT-,1n^ :]*:l:::,::
nrolled and complete the initialtreatment period'
clinical and immune endpoints will be evaluated in an exploratory
ner only using the following criteria:
and
secondary objective of this study is to determine the safety and toxicity of
*uinrtion lpilimumab .no nign-oose lL-2. The type, frequency and severitycf
nexpected adverse events witt ne noted in the intention-treat population' An
iteriiii safety analysis will be conducted after the first 6 patients are enrolled' An
ndependeni OSfrrf-g will review the safety data and if concerns are found the
oilimumab dose will be reduced to 3 mg/kg'
Protocol;APlrasellsrrrgleArrrrSjttrclyofHiglr.DoselL.SalrdlpiliurrrnmlrirrPafierrtrr.r'itlrUru.eseclable
Stage III and Stage tv![SSgEl,l-
,'j;" U"i i,,t-rt i!u tor, f
Plotocol \iersiott Date: I I Atrgrnt 1f116: \:erstou: 4'0

stics
protocol: A Phase iI single .{flu Sttrcly of Hig,h-Dose IL-l zurel Ipilirmurrab i[ Patieuts rvith urueseclable
Stage IIl and Stage tvIElSllE3S-
"oxicities will include abnormal hematology and biocheTitly laboratories' which
Ill be recorded at oasetlne and at ,rriout time points throughout the- study'
rerse events will be listed by subiects within groups showing time of onset,
iod of event, grade ctassirci using the CTCAE v'4'0' relati"T,h'1P^9':t:::
':r1[;:j.'#""rr*o*t of everits in each classification of severity and
ionship to treatment wrtt oe tabulated for each patient and summarized by
cont):
t$ffialresponseswillbeprimarilybasedon',1".!r*1
magnitude of cettutai ieipont"u. The frequency of effector CD8+ T cells and
rtatory cD4+FoxP3+ Tregs will be measured pre-treatme"l:11:t,:T:::
ffilil;;r.".i'i. 
the tu"nror (when feasible) and peripheral blood lmmune
;ponse for each patient will be measured as paired 1'.I::1":t^L:YT:i:?
fffiil;"Jrffi'J;ts of these parameters at various times Transformation of
re data will be perroimed if appropriate, e.g. log transforrnation, and hence
nt arm
I Responses
effect will be expressed on a log scale
ession-free and lyq3lljgylygl will be assessed u sing 
. Kapla', M:i:l g:l:
: 
lrt estlmate and report the median survival
s well as one year. two year and three year overall survival rales and their 900/o
fidence intervals.
I I Atrgrrst ?fJl6: \:ersiorr: 4,0
will be determined by immune-related response
(,"wHo). Disease iontrol rate (DCR) will include complete response'
,"iponru'und stable Jit"rt* Best overall response will also be recorded'

protocol: A P'ase Ii Si*gle A,rl snrdy of High-Dose IL-l a.d lpilirmr'rntr i* Patieu* rvith L'uesectable
Srase III artd Staqe l\' \lelanonra
I
1. INTRODUCTION
1.1 Research HYPothesis
Melanoma is the most serious form of skin cancer and accounts for 800/o of all skin
cancer-related mortality. Despite considerable research efforts' the median survival for
patients wrth metastatic melanoma is approxirnately 6-9 months' High-dose lL-2 induces
objective clinical responses in 16-17o/a of patients and results in durable complete
responses in 7-10olo of melanoma patients. The mechanism of anti-tumor activity with
high-dose lL-2 is not completely understood but recent data has suggested a correlation
of therapeutic response with cD4+FoxP3+ regulatory T cell (Treg) frequency' pre-
treatment serum biomarkers (e.g. VEGF. fibronectin) and host gene polymorphisms
supporting a role for immune-mediated tumor rejection t1-31' High-dose lL-2 (Proleukin)
was approved for the treatment of metastatic melanoma by the FDA in 1998'
cytotoxic T-lymphocyte associated protein (CTLA)4 belongs to a negative homeostatic
control mechanism regulating T cell activation. Preclinical studies of anti-cTlA-4 mAb
demonstrated the CTLA-4 blockade allows activation of effector cD8+ T cells resulting in
therapeutic anti-tumor responses [4]. A recent prospective, randomized Phase lll clinical
trial of an anti-CTLA-4 monoclonal antibody, lpilimumab (Yervoy) administered alone or
in combination with an HLA-A2-restricted gp100 peptide vaccine demonstrated
significant improvement in overatl survival compared to vaccine alone (10'1 months vs'
6.4 months, hazard ratio for death 0.66, P=0.003: 10'0 vs. 6.4 months, hazard ratlo for
death 0.68, P<0.001, respectively) [5]. Based on these data' Yervoy was approved for
the treatment of unresectable stage lll and stage lV metastatic melanoma by the FDA in
2011.
Melanoma is the 5m most prevalent cancer in the United States and accounts for
approximately 5 percent of all skin cancers. However, melanoma is responsible for 80
percent of all skin cancer related deaths. The incidence of rnelanoma is rising rapidly
and it is estimated that 6g,130 people were diagnosed with and about 8,700 people died
of melanoma in 2010. The median overall survival for patients with metastatic disease is
approximately 6-12 months. There are three FDA approved agents for the treatment of
metastatic melanoma. Dacarbazine (DTIC) is an alkylating agent that was approved in
1974. DTIC results in obiective responses in 5-2Oa/o of patients but the median duration
of response is generally 6 months [6]. ln 1998 high-dose bolus lL-2 was approved for
melanomaandinducesobjectiveresponsesin15-20o/t,"f@
Protocol \-elsiort Date: ll .'\trgtr'r lfil(': \'ctstort J ri

Protocol:APlnseIlSrrrgle.AlruSrucl.vofHiSlt-DoselL.]andlpilirrirrrrrolrirrPatielrtrrvitlrLlruesectable
Stase III artd Staee IV i-.lelartonta
I
associated with durable complete responses in 7-1 |a/r: of patients' ln 2011 the anti-
CTLA-4 monoclonal antibody lpilimumab was approved based on randomized Phase lll
data demonstrating a survival benefit when compared to p6ptide vaccine therapy' A
large number of randomized clinical trials have been performed combining lL-2 with
cytotoxic chemotherapy regimens but s0-called biochemotherapy has not demonstrated
asurvivalinanyprospectiverandomizedclinicaltrial[7.12]'
1.2 Product Development Rationale
The rationale for lL-2
ln the late 1970',s it was shown that human peripheral blood lymphocytes exposed to lL-
2 resulted in the generation of lymphocytes (lymphokine-activated killer' LAK' cells)
capable of lysing fresh autologous tumors in vitro [13]' This observation was followed by
in vitro data demonstrating regression of pulmonary metastases from transplanted
murtneSarcomaandBl6melanornatumorcellsinmiceinjectedwithlL-2.stimulated
tymphocytes [14]. Subsequent studies showed the ability of directly administered' high-
dose lL-2 to generate LAK cells in mice, and to mediate regression of established
metastatic deposits, although a strong dose-response relationship was not observed
ll sl
Afler performing phase I studies confirming the safety of lL-2 and the adoptive transfer of
LAK cells, a pilot study of the combination in the treatment of advanced cancer was
publishedinlgsS[16].Rosenbergetal.treated25patientswithaVarietyofrefractory
tumors, including 7 with rnelanoma. Partial responses were seen in 11 of the 25 patients
(7 of 11 had melanoma), and complete tumor regression was seen in one patient with
metastatic melanoma. Encouragingly, the responses seemed to be durable' Lotze et al'
described the treatment of ten patients with metastatic cancer with high-dose bolus lL-2
alone[lTl.Threeofthesixpatientswithmelanomahadobjectivediseaseregression,
while no responses were seen in those patients with colorectal or ovarian cancer'
Biopsyofregressinglesionsrevea|edamarkedlymphocyticinfiltrate.Subsequently'the
Samegrouppublisheddatacollectedinthetreatmentofl5Tpatientswitheithersingle-
agent high-dose lL-2 or lL-2 plus autologous transfer of LAK cells [18]' Of the 106
patients treated with combination therap!,21.6a/o had an objective response including
7.50/o who had complete responses. Meanwhile, 46 patients were treated with lL-2
Protocol \tersiort Date: I I August J(Jl6: \:ersion: 4 0

Protocol: A Plrase Ii Sirrgle furlt Study rrf High.Dose IL-] arrd lpililnrrrrrab in Patiertts r.vitlr Uruesectable
Srase III atrd Stase IV l{elartotna -
;*il\;l;;;'.'tisato.I
alone. one patient (2'1o/o) had a CR, and 10.8% had partial responses, for an overall
response rate of 13y0. ln both cohorts, complete responses were of prolonged duration'
on this basis, a series of clinical trials investigating the efficacy of single-agent high-
doselL.2wereperformedbetweenlgs5andlgg3'al22institutionsincludingthe
surgical Branch of the National cancer lnstitute and elsewhere' Rosenberg et al-
evaluated 409 consecutive patients with melanoma or renal cell cancer treated with
intravenous bolus lL-2 (720,000 lu/kg every eight hours, up to 14 doses over 5 days) at
the National cancer lnstitute from 1985 to 1996 [19]' ln an updated analysis of this
cohort through the fall of 1g96, with follow-up ranging from 3 to 11 years, the overall
response rate was 160/o, including 17 complete responses (60lo) [19]. of the 117o/o ot
melanoma patients who had a complete response, 83.3Yo remained in an ongoing
continuous remission at the time of publication, from 70 to 148 months' ln the extramural
clinicaltrrals,atotalof2T0patientswithmetastaticmelanomaweretreatedwithlL-2at
doses ranging from 360,000 to 720,000 lU/kg, intravenously over 15 minutes every 8
hours for up to 14 consecutive doses over five days as tolerated' with maximal
supportive care including pressors t201. A second treatment cycle was administered afier
6 to 9 days of rest, with further course given every 6 to 12 weeks in stable or responding
patients. Median duration of response was not reached at time of analysis for those
achieving a complete response, and was nearly 6 months for those with partially-
regressed disease. Responses were seen in all sites of disease and in patients with
heavy tumor burden. Median survival for the total group was 11'4 months' and with a
median follow-up of more than 5 years, nearly half the responding patients were still
alive, with 15 having survived more than 5 years. on the basis of these studies' and
particularly the extended duration of observed complete responses, the Food and Drug
administration approved the use of high-dose bolus lL-2 for the treatment of metastatic
melanoma in 1ggg. Further follow-up on these pivotal studies suggested that patients
can achieve durable long-term benefit from lL-2' After a median follow-up time for
surviving patients that exceeded 7 years, the median duratton of response for 43
responding patients and the 26 patients with partial responses in the pivotal lL-2 trials
remained unchanged at g.g and 5.9 months. respectively [21]. Response durations
ranged from 1 .5 to > 122 months and diseaSe progression had not been observed in any
patient who was responding as of the last report or in any patient responding for longer
than 30 months. [21].
Prntocol Velsion Date: l1 Atrgust 3016: Version: 1 0

prorocol; A Phase II Srngle Amr Stucil' of Hig,h-Dose IL-l alld lpilil}lru1lab in Patie[ts $'ith Lhuesectable
Stase III anrl Stage I\'I{elatrouta -
P*,i. irr. f i,tt='oti ga tot, I
ln these eArly trials, the most severe toxicities were related to a vascular leak syndrome
that resembled the manifestations of septic shock' sixty-four percent of patients
experiencedhypotension.whilelYosufferedgrade4hypotension.othersevere
toxicities rncluded mental status changes, tachyarrythmias, and respiratory events' but
these were rare, occurring in less than 4olo of patients' Nausea' vomiting' and diarrhea
were common, but were not life-threatening- Elevations of serum creatinine and bilirubin
were frequent but did not lead to chronic organ dysfunction' lnfections were seen in
15oA of all patients, with bacterial sepsis due to staphylococcus aureus leading to 6
treatment-related deaths. ln 1990, antibiotic prophylaxis became standard practice
duringlL.2therapyandtreatment.relatedmortalitydecreasedsignificantly[22].There
are now well established treatment guidetines for the prevention and management of lL-
2-related toxicity t23l Of note, the investigators on this protocol are all highly
experienced lL-2 clinicians.
Rationale for targeting CTLA-4 in Melanoma
The activation of T cells is a complex and highly regulated process that begins when a T
cell receptor recognizes its cognate antigen in the form of a processed peptide bound to
a major histocompatibility complex (MHC) on the surface of a professional antigen-
presenting cetl (APC). This interaetion has been termed "signal 1" and complete T cell
activation occurs only when a second co-stimulatory signal or "signal 2" occurs' This is
best characterized by the 87.1 and 87.2 co-stimulatory molecules on APCs that bind to
CD2g on the surface of a T cell. CD2g induces cell cycle progression, T cell proliferation
and production of tL-2. Foltowing activation. the cytotoxic T lyrnphocyte antigen 4 (CTLA-
4) is mobilized to the cell surface and inhibits T cell activation (see Figure 1)' CTLA-4
mediates T-cell inhibition through competition with cD28 for 87 and through specific
inhibitory signaling 124-311. ln addition to inhibiting effector T-cell activation and
proliferation, CTLA-4 engagement also results in down-regulation of lL-2 gene
transcription. This immunologic "checkpotnt"limits T cell activation to areas where there
is inflammation or injury mediatrng peripheral tolerance that protects normal tissue and
tumor cells against adaptive immune responses [32]' The potential antitumor effects of
CTLA-4 blockade were confirmed in preclinical tumor models where administration of
cTlA-4-blocking antibodies resulted in the regression of several highly immunogenic
tumor tYPes in mice [33-34].
Ptotocol \:ersiott Date: I I August 1016: \tersiorl: -1 0

protocol: A Phirse il single -{rru stucly ot High-Dose IL-3 artd Ipilirmrmatr ill Patiellts $'ith Lhueseclable
Srase III artd Stase IV Irlelauortta
I
However, CTLA4 antibody blockade alone has had minimal effects in the poorly
immunogenic 816 melanoma unless CTLA-4 blockade is combined with vaccination with
GM-CSF 135-371. This suggests that in eome tumors that have been heavily
immunoedited, or are poorly immunogenic. CTLA-4 blockade may need to be combined
with other strategies. The rmmunological studies suggested the GTLA-4 blockade alone
may potentiate both Tregs and effector T-cells. whereas CTLA-4 blockade coupled with
GM-CSF shifted the ratio of tumor speciflc T effector to Tregs [38-39]' These
encouraging data led clinical anti-cTlA4 antibody trials in cancer patients' lpilimumab'
a fully humanized (human) monoclonal antibody' demonstrated antitumor activity in
patients with advanced melanoma response rates range from about 5olo to 29o/o by
standard RECIST or wHo response criteria as monotherapy or in cornbination with
chemotherapy t40-431. Recent clinical data suggest that patients with advanced
melanoma benefited from 4 dosage of ipitimumab at 10 mglkg injected every 3 week
with prolonged median overall survivalfrom 8.9 to possibly longer than 15'5 months [44-
46l.Furthermore,withipilimumabtreatedpatientswithstablediseaseandthosewith
slow regression that did not meet strict RECIST or WHO criteria for response have had
prolonged time to progression. ln a prospective, randomized Phase lll clinical trial of an
anti-cTLA-4 monoclonal antibody, lpi[mumab (Yervoy) administered alone or in
combination with an HlA-Az-restricted gp't00 peptide vaccine demonstrated significant
improvement in overall survivalcompared to vaccine alone (10'1 months vs' 6'4 months'
hazard ratio for death 0.66, P=0.003, 10.0 vs. 6.4 months, hazard ratio for death 0'68'
P<0.001, respectivelv) t5l. Based on these data. Yervoy was approved for the treatment
of unresectable slage lll and stage lV metastatic melanorna by the FDA in 2011'
Protocol Versiott Date: I I Atrgust 1016: \iersrr:n: '1 tl

Protocol: A Phase II Sincle Arn study of Hig,h-Dose IL-l ald Ipilirnrrmab in Parienrs u,irlr Urueseoable
Stage III and Siage IV N,lelzurorla
Pritcipal hrtestigaton f
1.2.1 CTLA-4 and T Ceil Activation
Figure 1 Mechanism of Action
T q*ll tile{:tr$eitsrs
4..1
Advances in the understanding of the mechanisms that regulate T cell activalion have
allowed the rational design of new strategies for immunotherapy of tumors, including
melanoma. lt has been known for some time that engagement of the T cell antigen
receptor by itself is not sufficient for full T cell activation; a second co-stimulatory signal
is required for induction of lL-2 production, proliferation and ditferentiation to effector
function of naive T cells. Abundant data now indicate that the primary source of this
costimulation is mediated by engagement of CD28 on the T cell surface by members of
the 87 family on the antigen-presenting cell (APC) [47]. (See Figure 1.)
Expression of 87 has been shown to be limited to "professional" antigen presenting
cells; that is, specialized cells of the hematopoietic lineage, including dendritic cells,
activated macrophages, and activated B cells. lt has been suggested that this sharply-
defined restriction of 87 expression is a failsafe mechanism for maintenance of
peripheral T cell tolerance, insuring that T cell activation can only be stimulated by
appropriate APCs [48]. The fact that tumor cells do not express 87 contributes to their
poor capacity to elicit immune responses [49-50].
The demonstration that induction of expression of 87 on many tumor cells by
transfection, transduction, or other mechanisms can heighten tumor immunogenicity led
to great interest in pursutng this as an approach to tumor immunotherapy. As
demonstrated in vivo in murine tumor models, the utllity of 87 expression as a
vaccination approach is limited by the following factors: (1) BTexpressing tumor cell
vaccines are only effective when the tumor cells have a high degree of inherent
immunogenicity; (2) while B7-expressing vaccines have been shown in many cases to
be effective in inducing protective immune responses, they have dernonstrated only
limited utility in inducing responses to established tumors, and (3) inactivation of tumor
Protocol \:ersioa Date: I I Aueust 10i6: \:ersron: 4.0
tr fiell llctiY*i?tsil
T ccll Astlrrrli$n
II
i1
ti

Protocol: A Plnse II Single furtt Stucly of Hieh-Dose IL-? anrl Ipilirnrurmb in pafierrts r.vith unresectable
Stage III arrd Stage IV lr.lelauonm
Pliucipal Iltestigator, f
cells by radiation has been shown to destroy the immuno-enhancing activity of the 87
gene product [51-52].
ln the past few years it has become apparent that co-stimulation is even rnore complex
than originally thought. After activation, T cells express CTLA-4, a close homologue to
CD28. CTLA4 binds members of the 87 family with a much higher affinity than CD2B
[53]. Although there was initially some controversy as to the role of CTLA-4 in regulating
T cell activation, it has become clear that CTLA-4 down-regulates T cell responses [54J.
This was initially suggested by the following in vitro observations: (1)blockade of CTLA-
4/87 interactions with antibody enhanced T cell responses; (2) cross-linking of CTLA-4
with CD3 and CD28 inhibited T cell responses: and (3)administration of antibodies to
CTLA-4 in vivo enhanced the immune response to peptide antigens or superantigens in
mice [55-58J. Blocking CTLA4-87 interaction while preserving signaling via CD2B
resulted in enhanced T cell responses in uitro [56].
Perhaps the most convincing demonstration of the down-regulatory role of CTLA-4 came
from examination of mice with a null mutation [59-61]. CTLA4 knockout mice appear to
have spontaneously activated T cells evident at approximately 1 week after birth,
followed by rampant lymphoproliferation and lymphadenopathy. These mice die at
approximately 3 weeks of age, either as a result of polyctonal T cell expansion and
tissue destruction or as a result of toxic shock resulting from lymphokine production by
the T cells. Since thymocyte differentiation and selection proceed normally in
CTLA4deficient mice, the rampant T cell expansion that occurs in the mice indicates that
CTLA4 plays a critical role in down-regulating T cell responses in the periphery [58].
1.3 Summary of Results of lnvestigational Program
1.3.1 Pharmacology of lpilimumab
lpilimumab is a human immunoglobulin G (lgG1)x anti-CTLA4 monoclonal antibody
(mAb). ln vitro studies were performed with ipilimumab to demonstrate that it is specific
for CTLA4, actively inhibits CTLA-4 interactions with 87.1 and 87.2, does not show any
cross-reactivity with human 87.1, 87 .2 negative cell lines, and stains the appropriate
cells without non-specific cross-reactivity in normal human tissues, as demonstrated by
immunohistochemistry. lpilimumab does cross-react with CTLA-4 in non-human
primates including cynomolgus monkeys.
lpilimumab was originally produced and purified from a hybridorna clone. Subsequenly,
a transfectoma (CHO cell) has been generated that is capable of producing more
ipilimumab on a per cell basis than the hybridoma. Material from the transfectoma will be
utilized in this and fulure ipilimumab clinical studies. Biochemical, immunologic and in
vivo preclinical primate assessments demonstrated simrlarity between hybridoma and
transfectoma-derived ipilimumab.
August 1016: \:ersiol: 4.0

Protocol: A Phase II sirrsle ,{:rn Study of High-Dose IL-l ald Ipilirnruunb il patieltE n,irh Lhu.esec-lable
Stage III arrd Stage I\,'lr.lelauonra
Pnncipal Ltr.estigator: f
1.3.2 Pre-Clinical Toxicology of lpilimumab
Complete information on the pre-clinical toxrcology studies can be found in the
lpilimumab lnvestigator Brochure (lB). Non-clinical toxicity assessments included in vitro
evaluation for the potential of ipilimumab to mediate complement-dependent cellular
cytotoxicity (CDCC) or antibody-dependent cellular cytotoxicity (ADCC), and toxicology
assessments in cynomolgus monkeys alone and in the presence of vaccines.
The in vitro studies demonstrated that ipilimurnab did not mediate CDCC of pHA- or
(CD)3-activated human T cells. However, low to moderate ADCC activity was noted at
concentrations up to 50 ug1mL. These data are consistent with the requirement of high
levels of antigen expression on the surface of target cells for efficient ADCC or CDCC.
Since ipilimumab is a human lgGl, an isotype generally capable of mediating CDCC and
ADCC, the lack of these activities is likely due to a very low expression of CTLA4 on
activated T cells. Therefore, these data suggest that ipilimumab treatment would not
result in depletion of activated T cells in- vivo. lndeed. no depletion of T cells or T cell
subsets were noted in toxicology studies in cynomolgus monkeys.
No mortality or signs of toxicity were observed in three independent 14-day intravenous
toxicology studies in cynomolgus monkeys at multiple doses up to 30 mg/kgidose.
Furthermore, ipilimumab was evaluated in sub chronic and chronic toxicology studies rn
cynomolgus monkeys with and without Hepatitis B (HepB) Vaccine and Melanoma
Vaccine. lpilimumab was welltolerated alone or in combination in all studies. There were
no significant changes in clinical signs, body weighl values, clinical pathology values or
T cell activation markers. ln addition, there were no significant histopathology changes in
the stomach or colon.
1.3.3 Human Pharmacokinetics of lpilimumab
Pharmacokinetic (PK) profiles for ipilimumab have been analyzed. The primary ob.iective
of Protocol MDX010015 was to determine the safety and PK profile of singte and
multiple doses of ipilimumab derrved from a transfectoma or hybridoma cell line. Mean
plasma concentrations of ipilimumab administered at doses of 3 mglkg (hybridoma-
derived drug product); 2.8 mg/kg, 5 mg/kg. 7.5 mg1kg, 10 mg/kg, 15 mg/kg, and
20 mg/kg (transfectoma-derived drug product) demonstrated approximate dose
proportionality. Equimolar doses of hybridoma-derived and transfectoma-derived drug
product had comparable PK profiles. The range of mean volume of distribution at steady
state (Vss) across cohorts 2.8, 3, 5, 7.5. i0, 15, and 20 mg/kg, was 57.3 to 92.6 ml/kg,
indicating drug distribution was mostly limited to the intravascular space. The clearance
was low (range 0.11 to 0.29 mUh/kg) and reflective of the half-life (range 297 lo414hl,
which is consistent with the long terminal disposition phase of ipilimumab. There was
rnoderate variability in the PK parameters among subjects, with CV of 11a/o to 48olo in
AUC(0-21d\.20o/o to 59o/o in CL, and 17o/o to 460lo in Vss.
Plotocol \,'ersion Dare: I I Ausnst 3016: \:ersiol: 4,0
Page ?l

Protocol; A Philse II Silgle Artn Snrcll'of High-Dose IL-l ald lpilirnruuatr in Parierrrs u,irlr Lhu.esectable
Stage III and Stage IV \,{elauoma
PrmcipaI Lr.,'estigator, f
1.3.4 Clinical Safety with lpilimumab
lpilimumab immunotherapy is currently under investigation in patients with unresectable
advanced melanoma (unresectable Stage lll or Stage lV) to potentially demonstrate an
improvement on a large unmet medical need in this population.
lpilimumab has been administered to approximately 2901 patients with different cancers
in 25 completed or ongoing clinical trials as of 31-Mar-2009 with a dose range between
0.3 mglkg and 20 mglkg and in various combinations.
ln general, the safe$ profile of ipilimumab administered as single doses of up to
20mg/kg and multiple doses of up to 10 mg/kg every 3 weeks was characterized by
adverse reactions that were mostly immune in nature. Drug-related SAEs were reported
tn studies of rpilimumab admrnistered as monotherapy. as well as in cornbination with
vaccines, cytokines, chemotherapy, or radiation therapy.
The overall summary of safety for the 2901 patients treated with ipilimumab in the
completed or ongoing clinical trials and the subset of 658 patients treated at the 10
mg/kg dose level is presented in Table 1.
Table 1; 
lpilimumab l Ove_raf! Sumrnary of S_afefir
Number of Subjects (%)
lpilimumab 0.3 - 20
mglkg
N = 2901
lpilimumab 10 mglkg
N=658
{ny Drug-related AE
23s7 (81.2)
561 (85.3)
Grade 1
699 (24.1)
158 (24.0)
Grade 2
889 (30.6)
1e8 (30.1)
Grade 3
61 7 (21 .3)
163 (24.8)
Grade 4
127 \4.4j
38 (5.8)
Grade 5
20 (a.7)
4(06)
Any Serious Adverse Events
1258 (43.4\
310 (47.1)
Grade 3 - 4
806 (27.8)
179 127.2)
Any Drug-related Serious Adverse Events
s95 (20.5)
179 127.2)
Grade 3 - 4
46e (16.2)
140 (21.3)
August 1016: \'ersron: 4.0

Protocol: A Phase II sui-ele Ann snrdy of High-Dose IL-2 ald Ipilirnumnb in patieuls u,irh Lhu.ese*able
Stage III and Stare IV lr,{elanorna
PrurcipaI 1,n'estiSator, f
1 . 3.4. a Defails of D ru g -Related .Adyerse Eyenfs
Treatment-emergent adverse events (AEs) considered by the investigator to be related
to study drug were reported for 81 .2a/0 of all treated subjects and g5.3% of subjects
treated with ipilimumab at 10 mg/kg.
Among all treated subjects, the most frequently reported treatment-related AEs of any
grade included fatigue (27 .Byo). diarrhea {27.Sa/o), nausea \23.4a/a), rash (21 g%),
pruritus (19.99o), pyrexia (1 1 .9olo), and vomitin g (11 .To/oJ.
Similarly, among subjects treated with ipilimurnab at 10 mg/kg, the most frequenly
reported treatment-related AEs of any grade included diarrhea (3g.1%), fatigue (30.5yo),
rash (34.5olo). pruritus {29.8o/o), nausea (17.60/o), pyrexia {12.3a/a), vomiting (10.9yo). and
colitrs {10.2o/o).
1.3.4.b oetafls of Drug-Rerated serious Adverse Evenls
Among all 2901 treated subjects, SAEs considered possibly, probably, or deflnitety
related to study drug were reported for 20.5olo of subjects. Drug-related SAEs reported in
at least 1a/o of the 2901 subjects included diarrhea (5.8olo), colitis (4.7o/o),ALT increased
(2.39o), AST increased (2,2a/o), pyrexia {1.6yo), and vomiting (1.3yo). Among the 658
subjects who received ipilimumab at 10 mg/kg, SAEs considered possibly, probably, or
definitely related to study drug were reported for 27.2o/a of subjects. Drug-related sAEs
reported in at least 1o/o at the 658 subjects treated at 10 mg/kg included diarrhea (g.50/o),
colitis (7.Oolo),vomiting (2.1o/o), AST increased (2.1a/o), ALT increased (2.0o/o),
autoimmune hepatitis (2.aa/s), pyrexia (1.gyo), hypopituitarism (1.lyo), dehydration
(1 .74/<'), nausea (1 .Za/a), and abdominal pain 11 .1o/a).
1.3.5 lmmune-Related Adverse Events (irAEs) with lpilimumab
Many of the adverse events considered related to ipilimumab may be immune in nature
and presumabty a consequence of the intrinsic biological activity of ipilimumab. An irAE
is defined as any adverse event associated with drug exposure and consistent with an
immune*mediated event. Disease progression. infections and other etiologic causes are
ruled out or deemed unlikely as contributing to the event. Supportive data, such as
autoimmune serology tests or biopsies, are helpful but not necessary to deem an event
an irAE. Events of unclear etiology which were plausibly "immune-mediated" have been
conservatively categorized as irAEs even if serologic or histopathology data are absent.
These irAEs likely reflect a loss of tolerance to some self antigens or an unchecked
immune response to gut or skin flora. some breakthrough of immunity may be
inseparably linked to the clinical antitumor activity of ipilimumab.
lmmune-related AEs predominately involve the Gl tract, endocrine glands, liver or skin.
I I August l0l6: \:ersrorl J.0

Protocol: A Phase II Silgle Anu Stucl1.o1 High-Drise IL-l arrd
Stage III aud Srare IV lrlelnnonra
Pnncipal Ltlestigator: f
Among all 2901 treated subjects, 5g.6go (1TZgt2gO1) of subjects reported any irAE and
15'2a/o (44112901) of subjects reported serious irAEs. Among subjects who reeeived
ipilimurnab at 10 mg/kg ,21 .9o/a (144165g) of subjects reported serious irAEs.
Table 2 summarizes the incidence of serious irAEs among all treated subjects and
subjects who received ipilimumab 10 mg/kg.
aBased on treatment-related adverse events relrieved from the clinical database using pre-
defined MedDRA terms that were considered potential irAEs.
With few exceptions, irAEs were clinically manageable and reversible with supportive
care or corticosteroids. Management algorithms are included in the lB.
Corticosteroid treatment did not adversely affect antitumor responses in those subjects
who had both an irAE requiring steroid therapy and an objective tumor response.
Systemic corticosteroids do not appear adversely associated with ipilimumab-induced
clinical response when used to manage irAEs in patients with advanced melanoma.
Ipiliuiulmh iu Parieuts u,irh Lhu.esectable
irabre z:
Serious lmmune-related Adverse Events
Zoh at Subjects in any Event Category
Reported for at Least
Number of Subjects
AEsa
Any
Grade 3
Grade 4
;l irAEa
Any
%
Grade 3
limumab 0.3.20
N = 2901
441 (15.21
2eB (10 3)
s9 (2.0)
%
236 (8.1 )
166 (5.7)
limumab'10 r
N=658
144 (21.9)
s? {132)
25 (3.8)
85 (12.e)
%
58 (8.8)
Grade 4
17 (0 6)
10 (1 5)
-iver irAEa
Any
10s (3.8)
33 (s.0)
Grade 3
72 (2.5)
18 (2.7)
Grade 4
32 (1 .1)
13 (2.0)
indocrine irAEa
Any
61(2.1)
21 {3.2)
Grade 3
44 (1.5)
12 (1.81
Grade 4
3 {0 1)
1(4.2)
Protocol \,'errion Dale: I I Augu^st 1016: \:ersrou; 4.0

Protocol: A Phase II single fu'r:r snrdy of High-Dose IL-l alrl Ipilirnrurmb il patierrrr r.'irh Lhu.esecrable
Stage III and Stage IV Nlelalorna
Pritcipal luvestigator, f
Similar results were observed regardless of whether mWHO or the irnmune-related
response criteria (irRC) were used. Steroids can be used promptly to manage severe
irAEs and minimize the risk for serious complications [62].
ln the setting where subjects were enrolled to receive ipilimumab every 3 weeks dosing
until progression, irAEs could be reported at any time, with colitis and rash reported most
often during the early doses and hypophysitis reported with later doses.
Gastrointestinal irAEs
The most common Grade 3 or greater irAE involved the lower Gl tract and clinically
manifested as diarrhea or hematochezia. Diarrhea resulting from treatment with
ipilimumab ranged from mild to severe and was life+hreatening in some cases. some
cases of diarrhea beEan as mild and became very severe. Arnong subjects who received
ipilimumab at 10 mg/kg, GI irAEs of any grade were reported for 4O.Ao/o (263165g) of
subjects, and Grade 3 - 4 Gl irAEs were reported tor 12.60/o (83/6gS) of subjects. Serious
Gl irAEs, mostly involving diarrhea or colitis, were reponed in 12.ga/o (g5/65g) of subjects
treated with ipilimumab at 10 mg/kg.
lnflammatory Hepatotoxicity
lmmune-related hepatic dysfunction, including hepatitis or abnormal liver function tests
(LFT) attributed to ipilimumab therapy, has been reported. Subjects may develop
elevations in LFTs in the absence of clinical symptoms. lnflammatory hepatotoxicity
includes non-infectious hepatitis (eg, autoimmune hepatitis). Among subjects who
received ipilimumab at 10 mg/kg, inflammatory hepatotoxicity of any grade was reported
for 9.0olo (591658) of subjects, and Grade 3 - 4 inflammatory hepatotoxicity was reported
for 6.40/o (421658). Serious inflammatory hepatotoxicity has been reported in 5.0olo
(33/658)of subjects who received ipilimumab at 10 mg/kg. lnflammatory hepatotoxicity is
usually reversible when immediately treated with high-dose steroids, if applicable, with or
without additional immunosuppressants as recommended in the hepatotoxicity
management algorithm presented as an appendix in the lB.
Hypophysitis/Hypopituitarism and other Endocrine conditions
Hypophysitis/hypopituitarism, clinically manifested by fatigue. has been reported. Most
subjects with hypopituitarism presented with nonspecific complaints such as fatigue,
confusion, visual disturbance, or impotence. Some had headache as the predominant
presentation. The majority of subjects with hypopituitarism demonstrated enlarged
pituitary glands based on brain magnetic resonance imaging (MRl). Low
adrenocorticotropic hormone (ACTH) and cortisol were the most common biochemical
abnormality reported; low thyroid stimulating hormone (TSH), testosterone, or prolactin
was also reported in some subjects [63].
Protocol \ielsiorr Date: I I Arreust l0lfi: \'elsittrr -l 0
I
Page 1i

Protocol: A Phase II Single Anu Stucly of High-Dose IL-3 ald lpilrurrurrab il Parierrrr rvith Uru.eseuable
Stage III arrd Stage I\-Ntelalonra
-
Hypophysitislhypopituitarism was controlled with appropriate hormone-replacement
therapy and may be dose related" Among subjects who received ipilimumab at 10
mg/kg, endocrinopathy of any grade was reported for 7.69o (50/658) of subjects, and
Grade 3*4 endocrinopathy was reported for 2.4o/o (16/658) of subjects. Serious drug-
related endocrinopathy, such as hypophysitislhypopituitarism, was reported in 3.2olo
(211658) of subjects who received ipilimumab at 10 mg/kg,
The first onset of endocrine irAEs typically occurred between weeks 6 and 12 of
treatment. Endocrine events were generally manageable with hormone-replacement
therapy, and the majority of subjects were not weaned from steroids.
Rash and Other Skin Conditions
Rash was one of the most common irAEs, and most cases were Grade 1 or 2 in
intensity, pruritus has also been reported [64J. When biopsied, pleomorphic infiltrates
were noted in the skin. Among subject who received ipilimumab at '10 mg/kg. skin irAEs
of any grade were reported for 52.9o/o (34S1658) of subjects, and Grade 3 - 4 skin irAEs
were reported for 2.9a/o {191658) of subjects. Serious skin irAEs were reported in < 1olo
(4/658) of subjects who received ipilimumab at 10 mg/kg. Skin irAEs were generally
reversible.
Other presumed irAEs reported include, but were not limited to, arthritis/arlhralgias.
pneumonitis, pancreatitis, autoimmune (aseptic) meningitis, autoimmune nephritis, pure
red cell aplasia, noninfective myocarditis, occular inflammation. Guillain-Barre syndrome
(GBS), myasthenia gravis, and neuropathy (eg, motor neuropathy, neuritis), of which
were individually reported for < 1%o of subjects,
Other reported irAEs
Ocular inflammation, manifested as Grade 2 or Grade 3 episcleritis or uveitis, was
associated with concomitant diarrhea in a few subjects and occasionally occurred in the
absence of clinically apparent Gl symptoms [65]. Serious ocular inflammation was
reported in 1 of 658 (0.2Yo) subjects who received ipilimumab at 10 mg/kg (B [0.3olo] of
2901 subjects program-wide reported serious occular inflammation). preliminary
analysis (based on the manual extraction of the SAE data from the internal safety
database) indicated that the median time to event onset was approximately 61 days
(range: 14-114 days). Based on the available data with known outcome, most of the
subjects recovered or improved with or without corticosteroid therapy with a median
duration of approximately 6 days (range: 5 - 23 days).
Management algorithms for general irAEs, and ipilimumab-related dianhea,
hepatotoxicity, endocrinopathy, and neuropathy are presented as appendices in the
current lB.
,{.ugust 30I6; Version: {.0

Protocol: A Phase II Sui-ele Anrr snrcty of High-Dose IL-3 ald Ipilirnr.uuab in pafierrrs u.irh L.rru.esectable
Stage III aud Stage IV N.lelalroma
PrurcipaI Ln'estigator: f
Additionally, as of February 2006, there has been observation from a National Cancer
lnstitute (NCl) study of bowel wall perforation in some patients who were administered a
high-dose lL-2 following treatment with ipilimumab. of the 22 patients administered high-
dose lL-2, three patients experienced bowel wall perforations. This is a higher rate than
would be expected with high-dose lL-2 treatment alone. All three patients had metastatic
melanoma and had previously received their last dose of ipilimumab > 17 days before
the first dose of lL-2. Two of the patients had clinically significant ipilimumab-related
dtarrhea or colitis and the symptoms had completely resolved prior to lL-2
admintstration. one patient did not experience ipilimumab-related diarrhea. lt is unknown
whether this observation represents a true association or is mechanistically unrelated to
prior ipilimumab exposure.
1.3.5.a Drug-Related Deaths
Based on reports from the safety data base as of June 30, 2009, there have been
reports of death (approximately 1olo t35/38001), deemed by the investigator as possibly
related to the administration of study drug. The most common cause of drug related
deaths was Gl perforation. Other causes included multiorgan failure, sepsis,
hypotension. acidosis, and adult respiratory distress syndrorne. For details on all drug-
related deaths. refer to the current version of the lpilimumab lnvestigator Brochure"
1.3.5.b Safefy of 10 mg/kg Muttiple Doses
Based on a review of the program-wide SAE data as previously reported, evidence had
suggested that ipilimumab-associated irAEs were dose dependent in frequency, and
higher irAE rates had been observed at 10 mg/kg than at lower doses of ipilimumab.
subsequently, this dose-dependent effect was further demonstrated in cA1g4a22 in
which three dose levels of ipilirnumab were studied, including 0.3 vs 3 vs 10 mg/kg.
Table 3 summarizes the overall irAE frequencies by dose from CA1g4022 based on
safety data from the locked clinical database.
Qualitatively, the safety profile of ipilimumab at 10 mg/kg remains consistent with the
low-dose safety profile in that most of the drug-related SAEs are characteristic of
immune-related toxicity, and rnost of the irAEs are reported in the Gl, hepatic, and
endocrine systems. However, the data presented in Table 3 suggest that the frequency
of irAEs in association with 10 mg/kg of ipilimumab at multiple doses is higher compared
with the irAE frequency reported for lower doses.
Augrxt 1016: \.'ersion: 4.0

Protocol: A Phase I1 Single ,{rn snrcly of Hish-Dose IL-l aud Iliilirnrurrab in Parierris *'ir[ Lhu.esegable
Stage III anel Stage I\: llelarrorua
Prlrcipal bivestigator: I
Table 3.
Summary of lmmune-Related Adverse Events (irAEs)
by Treatment Groups - Treated Subjects (CA184022)
Number of Subjects (%)
lpilimumab
0.3 mglkg
(N=72|
3 mg/kg
(N;71)
'10 mg/kg
(N=711
CverallirAEs
Grade 3-4
26.4
0
64.8
7.0
I U.4
25.4
3lirAEs
Grade 3-4
16.7
0
32.4
2.8
39.4
15.5
{epatic irAEs
Grade 3-4
U
0
U
2.8
2.8
ndocrine irAEs
Grade 3{
U
0
5.6
2.8
4.2
1.4
Skin irAEs
Grade 3-4
12.5
0
45.1
1.4
46.5
4.2
1.3.5.c Neuropathies
lsolated cases of motor neuropathy of an autoimmune origin have been reponed among
patients treated with ipilimumab. Three cases have been diagnosed as Guillain-Barre
syndrome (GBS), two of which were considered study related. ln both cases. the GBS
was atypical in nature and more clinically resembled polyneuritis. As of 30 June 200g,
27 cases of neuropathy SAEs have been reported. Of these, ZZ were assessed as
unrelated to study therapy because alternative etiologies, including brain metastases,
spinal cord compression, arterial thrombosis, or platinum-base chemotherapy were
identified in almost every case.
1.3.6 Clinical Efflcacy of tpitimumab
Treatment with ipilimumab has demonstrated clinically important and durable tumor
responses in several malignancies including melanoma. prostate cancer, and renal cell
earcinoma. The most extensively studied tumor type has been malignant melanoma and
the principal demonstration of the efiicacy of ipilimumab at the 10 mg/kg dose comes
from 3 Phase 2 multicenter trials in 487 subjects with advanced melanoma: CAlg4A22
[66]. cA184008 [67]and CA184007 168I.
CA184022 was a dose-ranging trial in which subjects were randomized (1:1:1) to a high
(10 mg/kg) intermediate (3.0 mg/kg), and tow (0.3 mg/kg) ipitimumab dose. cA184022
and CA184008 enrolled pretreated subjects and efficacy data at 10 mglkg are pooled for
these studies; CA184007 enrolled a mixed population of pretreated and previously
Aug-ust l0l6: Version: ,1.0

Prr:tocol: A Phase II Sirrele ,furu Stttcly nf High-Dose IL-l ald lpiliuruuatr in patieuts rl,ith Ltru.eseclable
Stage III and Stage IV lr{elauorua
Prrrrcipnl hrvestigator: I
untreated subjects' ln all 3 studies, ipilimumab as monotherapy was administered by
intravenous (lV) infusion every 3 weeks for 4 doses (induction), followed by a dose every
1 2 weeks (maintenance).
The overall survival (OS) results from these 3 completed primary phase 2 studres are
presented in Table 4.
Table 4
Updated Overall Survival Results for B primary Studies
in Advanced Metanoma (as of 09-Mar-2009)
'arameter
CA184022 , CA184008
--'''''-r-''''-*
All Randomizedr All Treated
I
, cAi84007
AllRandomizeda
lpilimumab
10 mglkg
N=72
lpilimumab 10
mglkg
frl = '155
lpilimumab
10 mglkg +
Placebo
N=57
lpilimumab
10 mglkg +
Budesonide
N=58
3S. Median (Months)
l5Yo Cl (Months)b
1 1.43
(6.90, 16.10)
14.22 r 
19.29
(7.se. 16.30) I tr r eg, --t
17.68
(6.80, --)
Survival Rate at 1 Year (%)
)5olo Cl (Yo)c
48.64
(36.84, 60 36)
47.22 t 
62.41
(3e 52, s5 11) I (aS sZ. 75.A7)
55.87
(42.71.68 7s)
Survival Rate at 2 Years (o/o)
,sqo ct(%)c
29.81
(19.13.41.141
32.83 t 
41.78
(25.37, 40.4e) I (ZA.SO, s5.46)
40.57
127.12, U.37)
a Data are presented for the per-protocol mixed population of pretreated and previously
untreated subjects.
b Based on Kaplan-Meier estimation and clcomputed using the bootstrap method.
c Median and associated 2-sided 950/o Cls calculated using the method of Brookmeyer and
Crowley.
Consistent with the known mechanism of action of ipilimumab, the reduction in tumor
burden in the 3 primary melanoma studies was characterized by novel patterns of
measurable clinical effect. ln addition to objective response (complete response [CRJ
and partial response tPR]), and SD as measured by mWHO, novel patterns of clinical
activity, which are related to the immunological mechanism of action of ipilimumab, were
reported in all 3 studies. These patterns of activity were characterized by overall
reductions from baseline in total tumor burden (index plus measurable new lesions,
when present) afier the appearance of new lesions andlor after an initial tumor burden
increase. ln the phase lll clinical trial ipilimumab at a dose of 3 mglkg was associated
with an overall objective response rate of 10.9% tsl. Of 227 treated subjects who
received 10 mg/kg ipilimumab in studies CA184022 and CA184008, 9.7olo of subjects
I I August l0l6: \.'ersron: 4.Cl

Protocol: A Phase II Single .&tr Snrcly of High-Dose IL-3 arrl Ilrilinruuab iu pafierrts rl.ith Lhu.esecrable
Stage III arrd Stage [\'Nlelanoura
r
demonstrated disease control after an initial increase in tumor burden and/or
appearance of new lesions [66-68]"
survival data from these 3 primary studiBs (cA1s4022, cA1g400g, and cA194007) are
supported by OS data from CA184004 and MDX010-28. Both studies enrolled previously
untreated and pretreated subjects with advanced melanoma. ln CA184004, 42 subjects
were randomized to 10 mg/kg ipilimumab. The median follow-up for survival in this study
was 8.6 months. The rnedian OS was 1 1 .8 months (gSyo Cl: 6.1 , -); the 1-year survival
rate was 44.2o/o (95o/o Cl: 24.1o/o.64.10/o) [69]. Data are available for 23 response
evaluable subjects treated at 10 mglkg ipilimumab in MDX010-15 who enrolled in the
follow-up study MDX010-28. The median followup for survival in this study was 13.4
months. The median OS was 13.2 months (95% C|.9.4. 19.4). The overall survival for
2 subjects with ongoing responses was 26.0+ months and 25.0+ months [70].
Further details on clinical results can be found in the current version of the lpilimumab
lnvestigator Brochure.
1.3.6.a Relalions hip Between Response and lmmune Retated Events in
Patienfs with Metasfafic Melanoma
Drug-related AEs of any grade considered lo be immune-mediated in nature (irAEs)
were reported for 59.6a/o (172912901) of subjects in clinical studies of ipilimumab. These
irAEs are a consequence of inhibiting CTLA-4 function and most were reported as Grade
1 or 2. An association between best overall response (BORR) and higher grade (Grade
3-4) irAEs was suggested in early studies of ipilimumab 3 mg/kg but this association was
not obserued in 4 Phase 2 studies of ipilimumab administered at 10 mg/kg (CA184022,
CA184008, CA184007 and CA184004). There were proportionally more subjects with
irAEs of any grade who experienced response or stable disease than subjects without
irAEs who experienced response or stable disease. but due to the small sample sizes,
these observations were statistically inconclusive t66-681. Generally, disease control and
long term survival are observed among patients regardless of whether they do or do not
developGrade22irAEs.
Page -i0
Augnst l0l6: Versron: 4.0

Prt.rtocol: .{, Phase I1 Siugle furir Stucly c)i Hiell-Dose IL-l arrd Ipiiirnrurmb il Parierrrs *'irh Llru.esegable
Staee III and Stage I\'\lelanoura
r
1.4 Safety of lnterleukin-2
lnterleukin-2 (Proleukin; Aldesleukin) was approved for the treatment of metastatic renal
cell carcinoma in 1992 and for metastatic melanoma in 1998. There is now considerable
safety information available on lL-2 and clinical algorhythms have been established to
prevent and treat potential lL-2-related toxicity {72-731. All patients contemplating
treatment with lL-2 are screened for general clinical performance status, presence of
active tnfections, presence of CN$ metastases, cardiac stress testing in all patients over
50 years of age or in any patient with a clinical history or signs of underlying ischemic
heart disease and pulmonary function studies in patients with a history of pulmonary
disease, chronic smoking or extensive pulmonary metastases. These pre-treatment
studies help to identify patients who may experience high grade toxicity during lL-2 and
may exclude patients from treatment. The presence of active CNS metastases.
reversible ischemic heart disease, pleural effusions, ascites and active infection are
contraindications to lL-2 and such patients would not be eligible for participation in this
trial.
The major adverse events related to high-dose lL-2 treatment are due to capillary leak
syndrome. This is a constellation of physiologic changes characterized by hypotensron,
increased cardiac output, peripheral edema and multi-organ system dysfunction. The
toxicity is generally self-limited and effective management strategies are available. Most
patients will experience fever and chills with lL-2 administration but this side effect can
be prevented or blunted by prophylactic use of acetaminophen and indomethacin, which
are frequently given prior to lL-2 dosing. Hypotension can be treated with fluid challenge
and intravenous pressors in refractory situations. Cardiac dysrhythmias, such as atrial
fibrillation, can occur and a cardiomyositis related to lL-2 has also been reported.
Patients are typically treated on telemetry to monitor their cardiac rhythm and
dysrhythmias are treated through standard measures while cardiomyositis responds to
non-steroidal anti-inflammatory agents. Peripheral edema is usually limited and typically
responds to diuretics.
August f016: \:ersrorr: 4.0

Protocol: A Phase II Single ,\rn Snrcl1. of Hieh-Dose IL-3 arrd Ipilirntunatr in Pafierrrr t irh Llru.eseclable
Stage III and Stage I\-}\lelauorua
I
The Gl side effects tnclude nausea, vomiting, diarrhea, hepatic dysfunction,
hyperbilirubinemia, hypoalbuminemia and anorexia. Most patients are given anti-emetics
prophylactically and rnonitored closely during therapy for signs and symptoms of Gl
abnormalities. These symptoms typically resolve with treatment cessation and patients
can be supported by additional anti-emetics and anti-diarrheal agents if necessary.
Renal side effects include oliguria, electrolyte abnormalities and elevated serum
creatinine, which is usually monitored daily. Treatment usually involves fluid and
electrolyte replacement and doses may be held for an elevated creatrnine. These
abnormalities usually resolve when treatment is stopped and active dieresis may be
helpful in some cases. Additional side effects include neutropenia, thrombocytopenia,
pruritis, confusion. autoimmune thyroiditis and vitiligo. Laboratory values are monrtored
daily and patients are closely observed clinically during active treatment. All symptoms,
except for autoimmune thyroiditis and vitiligo, are temporary and resolve at the end of
treatment.
Of particular concern is the development of diarrhea since ipilimumab may also result in
autoimmune colitis and significant diarrhea. The mechanism of the diarrhea and kinetics
of response for the two drugs, however, is different. While ll-2-related diarrhea is
secretory in nature and occurs and resolves rapidly, ipilimumab-related diarrhea is
inflammatory in nature and develops more slowly. There is some evidence that patients
who receive ipilimumab following therapy with lL-2 do not have an increase in side
effects, including diarrhea (Kaufman et al. ASCO abstract 2013). A previous clinical trial
of lL-2 and ipilimumab also did not show any unexpected change in the frequency or
severity of diarrhea [43].
1.5 Overall Risk/Benefit Assessment
Results from 3 primary efficacy studies of ipilimumab in advanced melanorna suggest
thal the 10 mg/kg dose is active and offers the best benefit to risk ratio based on a rate
of disease control ranging tram27.1a/o to 35.1% and 2-year survival rates ranging from
29.81o/a lo 41.78a/o in the context of the historical data which demonstrate a Zyear
survival rate of approximately 8Yo to 18olo in subjects with previously untreated advanced
melanoma 174-771. Substantial reductions in total tumor burden, including widely
disseminated disease in the skin, lung, and/or other visceral disease sites, were
reported. More than half the responses were reported in subjects staged with M1b or
Mlc advanced melanoma disease, which is most resistant to approved therapies. The
Protocol Versiou Date: I I Ausust l{JI6: \'ersion: "{.0
Page -il

Protocol: A Phase II Single Arrt Srudy of Hieh-Dose lL-2 and Ipilirnruuob in Parierrtr r,irh Uru.esecrable
Stage Il1 arrd Srage IV N,lelauotna
Pnucipal hrvestigator: I
kinetics of ipilimumab resulted in known patterns of clinical activity (CR, PR and SD) as
well as novel patterns, characterized by reductions in total tumor burden, including
existing and new lesions, afier initial tumor volume increase andlor afier appearance of
new lesions. ln the pretreated population at 10 mg/kg in 2 of the 3 studies, disease
control after initial tumor volume increase andlor new lesions was reported for g.7% of
subjects. Across all 3 studies, stable disease was often accompanied by clinically
relevanl reductions in tumor burden compared to baseline. All patterns of response,
including SD, appeared to result in favorable survival, based on 1-year survival rates.
Characteristic organ-specific inflammatory irAEs were reported with ipilimurnab therapy,
typically during induction therapy. lrAEs were mostly reversible within days to weeks
following cessation of therapy or treatment with symptomatic therapy, corticosteroids or
other anti-inflammatory agents, depending upon severity. Accumulated clinical
experience resulted in detailed toxicity management guidelines (also termed algorithms),
by use of which irAEs can be effectively managed, especially when irAEs are recognized
early and subjects are treated in a timely fashion. This can minimize the occurrence of
irAE complications, such as Gl perforationlcolectorny or hepatic failure.
Treatment with ipilimumab resulted in clinical activity in pretreated and previously
untreated subjects with advanced melanoma. Clinically relevant reductions in the tumor
burden from baseline were reported, together with a preliminary evidence of improved
overall survival compared with published survival rates. These findings, together with
evidence of a safety profile that is manageable with careful monitoring and appropriate
intervention for treatment of immune-related toxicities, suggest an acceptable benefit to
risk ratio.
1.6 Study Rationale
The goal of this study is to determine if there is a clinical benefit to combining high-dose
lL-2 with ipilimumab rn patients with metastatic melanoma. A previous Phase llll clinical
trial was conducted to evaluate this combination in patients with metastatic melanoma
[43]. ln this trial, 36 patients received ipilimumab every three weeks for a total of three
doses in a dose escalation manner with three patients receiving 0.1, 0.3, 1.0 or 2.0
mg/kg. An additional 24 patients received ipilimumab at 3 mglkg, the MTD tested and
achieved in this trial. All patients received high-dose bolus lL-2 at 720,000 lU/kg every 8
Protocol Ver:iolr
n
Page -i-i
Date: I I Augrxt l0l6; \:ersrot: 4.0

Protocol: A Phase II Sitgle.{rrr Srudy of High-Dr:se IL-3 ald lliiiimuuali in Pafierrts lr,irfi Lhuesegable
Stage III and Staee IV I\lelauorrra
r
hours to a maximum of 15 doses. The lL-2 was administered immediately following the
second and third infusions of lpilimumab. This kial did not allow maintenance lpilimumab
treatment. of the 36 patients treated, 8 QZa/o) demonstrated objective tumor regresston
with 3 complete and 5 paftial objective responses. These responses included patients
with soft tissue and visceral disease. Six of the 8 patients were reported to have ongoing
objective responses al 11-19 months following the trial. There were five patients (14o/o)
who developed grade lll or lV autoimmune events following treatment and there were no
treatment-related deaths.
The NCI suggests that the combination is feasible and may be associated with
meaningful therapeutic responses with a comparable rate of autoimmune toxicity. This
study, however, may underestimate the potential of this combination for several reasons.
The maximum lpilimumab dose used was 3 mg/kg and there is now evidence that 10
mg/kg may be associated with a higher clinical response rate. Current data from
lpilimumab clinical trtals also suggests that a minimum of four cycles of treatment are
needed for induction and many patients benefit from maintenance lpilimumab
administration. Further, it is possible that responses may be delayed following
lpilimumab treatment and, thus later follow-up is required to fully determine the
therapeutic impact of treatment. Thus, this clinical trial will be designed to better define
the optimal dose and schedule of lpilimumab with appropriate clinical follow-up to better
determine the potential for combination treatment in melanoma.
The overall risk-benefit ratio for patients entering this protocol is therefore at least
comparable to and possibly better than alternative options. ln the current clinical trial, we
plan to confirm that the combination of high-dose lL-2 and lpilimumab will result in
improved clinical outcomes for patients with metastatic melanoma usrng a larger
cohotl of subjects and a higher dose of ipilimumab. We will also test the hypothesis that
combination ProleukinlYervoy is feasible and safe in patients with advanced melanoma,
induces tumor-specific immunity, and leads to long{erm T cell memory and inhibition of
CD4'CD25' regulatory T cells,
I I .A,ugust l0l6: \'ersir:rn: 4.0

Protocol: A Plmse II Single Arlr Snrdy of High-Dose IL-2 alcl Ipilirnumab il Patierrt* s,it5 Lhu.esecrable
Stage III and Stage IV ltlelalorua
Pnncipal hrtesti€,ator: f
2. STUDY OBJECTIVES
2.1 Primary Objective
The primary clinical endpoint will be the best overall response rate within the first 24
weeks of combination lL-2 and ipilimumab usrng the immune-related response criteria.
The rationale for this endpoint is based on recent data suggesting a delayed kinetic
pattern of tumor regression with immunotherapy agents, such as ipilimumab. The
combination is expected to result in more objective responses.
Preliminary safety assessment will be performed on the first 6 patients before other
patients are allowed o to enter the study
2.2 SecondaryObjectives
The following secondary objectives will also be determined in this trial:
Clinical Response
ln addition to the primary objective, secondary clinical endpoints of efficacy will be
collected in an exploratory manner as follows.
Best overallresponse @Afl: Since responses may exhibit delayed kinetics it is possible
that standard response reporting may miss a nontraditional tumor regression with the
planned reporting criteria. We will, therefore, collect the best overall response for each
subject at any point during their study involvement in case patients develop a delayed
response after the frsl24 weeks.
Progression-free survival (PFS). Progression-free survivalwill be assessed using Kaplan
Meier plots and based on mWHO criteria for disease progression. The progression-free
survival rates will be presented, together with the 90o/o confidence intervals. lf
appropriate, medians and g09o confidence intervalwill also be presented.
Dlsease control rate (DCR): Srnce it is known that PFS may be an inappropriate
endpoint for ipilimumab and other forms of immunotherapy, we will also collect data on
dr'sease control rate defined as the rate of complete, partial and stable dlsease
responses.
Averall survival: Overall survival will be assessed using Kaplan Meier plots at 1, 2 and 3
years.
Safefy and Feaslbtlity
Protocol
CN.T #
Page -15

Protocol: A Phase II Single fulr Stucly of High-Dose IL-? ald lpilirnunNltr irr Patieurs u,ilh LTru.esecrable
Stage III aud Srage IV Nlelanorua
Prrrrcipal hn'estigator: f
A secondary objective will be to collect data on the safety and feasibility of combined
high-dose lL-2 and ipilimumab. The type of toxicity, frequency and severity wilt be noted
in the intention-to-treat populatron. Toxicities will include abnormal hematology and
biochemistry laboratories, which will be recorded at baseline and at various visits
throughout the study. Adverse events will be listed by subjects within groups showing
time of onset, period of event, grade classified using ihe CTCAE v.4.0, relationship to
disease and outcome. The number of events in each classification of severity and
relationship to treatment will be tabulated for each patient.
Preliminary safety assessment will be performed on the first 6 patients before other
patients are allowed o to enter the study
lmmune Responses
To evaluate the CD4+ and CD8+ T cell response in the tumor microenvironment and
peripheral blood of patients treated on this study. Evaluation of immune responses will
be primarily based on the breadth and magnitude of T cell responses compared from
post-treatment with both agents to baseline levels. The frequency of activated effector
CD8+ T cells and CD4+ regulatory T cells will be measured pre{reatment and at
selected time points post-treatment in the peripheral blood, and in the tumor
microenvironment in selected patients who agree to and have easily accessible tumors
for serial biopsy. MART-1-specific CD8+ T cells will also be determined by tetramer or
dextramer analysis and selected patients (HLA-A2+; will have antigen-specific
responses determined by MART-1, 9p100 andlor tyrosinase tetramer analysis and
intracellular cytokine staining. ln non-A2+ subjects we will use overlapping peptides in an
interferon*gamma ELISPOT assay, or alternatively will perform intracellular interferon-y
staining. Treatment effect for each patient will be measured as paired differences
between pre- and post-measurements at each site. Transformation of the data will be
performed if appropriate, e.g. log transformation, and hence treatment effect will be
expressed on a log scale.
3. STUDY DESIGN
The study will be an open label, single arm trial in which patients will be treated as
ry,Dafe: 
ll.{irgust1016:\'ersrorr:.i.{J 
F

Protocol; A Phase II Single .\rr Stucly of High-Dose IL-3 ald Ipiliuurmab in Patierrtl with Uruesectable
Stase III .lrrd Stase I\'\telalronra
rt iilLltLtl 
ltiiF\tt-.ttrtl 
I
follows:
lnductionTreatment: lpilimumab (10 mg/kg) for 4 cycles (Days 1,22, 43,64) and high-
dose lL-2 (600,000 lU/kg) for 2 cycles (Days 22-26,43-47).
On days when both drugs are scheduled, the ipilimumab should be administered first
followed by lL-2 at least 4-6 hours later.
Beginning on week 24, patients without disease progression or unacceptable toxicity will
receive maintenance ipilimumab ("10 mg/kg) lV over g0 minutes. Treatment repeats
every 12 weeks in the absence of disease progression or unacceptable toxicity after the
treatment induction period and this does not pertain to afier maintenance ipilimumab
treatment.
The trialwill be conducted in three phases, as described below^
. Screening
During the screening phase, each patient will be assessed for eligibility to participate
as determined by the inclusion/exclusion criteria (Section 4). Patients will also
undergo baseline imaging, blood work, urinalysis, EKG and peripheral bloodltumor
(when feasible) collection for immune monitoring analysis. The informed consent
must be reviewed with the subject, signed, dated and the patient given a copy of the
signed consent form. Once the consent is signed, a copy will be submitted to the
Theradex@ IWRS sytem and a patient number assigned. This number will be used on
all case report forms for the subject.
AII patients must be registered in the TheradexCI lnteractive Web Response System
(IWRS). Patient enrollment information must be entered in the Theradex@ lnteractive
Web Response System (IWRS) prior to lirst study drug administration. This
information will serve to confirm patient eligibility and initiate the enrollment process.
Once the Theradex$ IWRS system verifies eligibility, a unique patient study number
will be issued. The patient will not be identified by narne. fhis is the point that the
patient is considered on study The patient will be considered on study as of lP start..
Protocol Veriou Date: I I August l016: \:erstou; 4.0

Protocol: A Phase II Single Arlr Snrcly of High-Dose IL-t aud Ipiliurrurrat.r in Pafierrtr u.irh Lhu.esecrable
Stage III arrd Stage IV tr{elauoura
Principal Ln'estigatc,l', f
Patients must not start protocol treatment prior to registration. See the $tudy
Operations Manual for further information on Patient Enrollment.
Patient demographic information, the signed
checklist and completed signature page of the
documents if requested by CINJ Regulatory
registration desk. Site should retain source
eligibilities, consents and registration papenvork.
Protocol Number
I nvestigator ldentifi cation
lnstitution and affiliate name
lnvestigator's name
Patient ldentification
Patient's initials and registration nurnber
Patient demographics
Sex
Birth date (mm/yyyy)
Race
Ethnicity
Nine-digit ZIP code
Method of payrnent
Elioibilitv Verifi cation
Patients must rneet all of the eligibility requirements listed in Section 4.0. An
eligibility checklist has been appended to the protocol.
Additional Requirements
Patients must provide a signed and dated written informed consent form.
Pathology repofis must be submitted as indicated in Section 12 tor review.
Blood and tumor samples are to be submitted for banking per patient consent as
indicated in Section 12
lnstructions for Patients who Do Not Start Assigned Protocol Treatment
lf a patient does not receive any assigned protocol treatment, baseline and
and dated study-specific eligibility
consent form and additional source
Coordinator must be sent to the
document copies of all original
Protocol Venioll Date: I I .{irsilst l0l6: \'ersron: 4.0

Protocol: A Phase II Si[gle .fuu Snrdy of High-Dose IL-] ancl lpilimruualr in Parientr u,irh Uru.e.secratrle
Stage III aud Srage IV lrlelanonra
r
follow-up data will not be collected. However, the reason for not starting protocol
treatment must be documented on the off treatment form. Also the date and type
of the first non-protocol treatment thal the patient receives will be reported
. lpllimumab lnduction
The recommended induction dose of ipilimumab as a single agent is 10 mg/kg
administered intravenously over a g0 minute period every 3 weeks for a total of
four doses, as tolerated.
Laboratory evaluations should be performed and the results examined before
administration of each ipilimumab dose.
As durable disease stabilization andlor objective tumor response can be seen
after early progression before Week 12, it is recommended that, in the absence
of dose limiting toxicities (e.9. serious irAEs), all four doses of ipilimumab be
administered over the initial 12 weeks even in the setting of apparent clinical
progression. providing the subject's performance status remains stable.
- All subjects who enter the induction period, including those who may have
discontinued treatment for drug-related AEs andlor who have evidence of clinical
progression during the induction period, should obtain a '12 week tumor
assessment.
* Based on clinical experience in the ongoing and completed melanoma studies,
the following recommendations apply for subject management in light of the
Week 12 or later tumor assessments.
Atrsust l0l6: Versiorl 1.0

Protocol: A Phnse II Single.l,:ru Snrcll'of High-Do:e IL-2 ald lpiliururnab il Patierrts u,ith thueseclable
Stage III and Stage IV lr{elanoura
Prrlcipal l,n'estigator, f
' 
The appearance of new lesions in subjects with other stable or shrinking baseline
tumor burden may be experiencing clinical benefit and should continue in follow-up
and/or maintenance therapy before alternative anticancer agents are considered.
These subjects can be seen to have continued tumor shrinkage in follow-up scans.
. As long as overall tumor burden is stable or decreasing, subjects should remain in
follow-up and/or maintenance (see below), even in the presence of new lesions.
. Clinical progression warranting alternative anti-cancer treatment should be
considered only in subjects whose overall tumor burden appears to be substantially
increased and/or in subjects whose performance status is decreased.
lpilimumab Maintenance As per the schedule of dosing in the ongoing and
completed clinical studies using ipilimumab in subjects with pretreated advanced
melanoma, at Week 24. maintenance therapy should be offered to atl subjects who
have not experienced unacceptable toxicity (refractory Grade > 3 irAEs) and are
considered by the investigator to be obtaining clinical benefit, either because of
apparent tumor stability or continued shrinkage and/or late response.
A single dose of 10 mg/kg ipilimumab given intravenously over 90 minutes should be
administered every 12 weeks, starting from Week 24 until the subject is no longer
clinically benefiting from therapy, per the investigator, or until the occurrence of
unacceptable or unmanageable toxicity.Subjects in maintenance should receive
radiographic tumor assessments every '12 weeks before administration.
I nterleu ki n-2 Treatment
lnterleukin-2 will be administered according to standard institutional guidelines
and in accord with current clinical practice guidelines for ll-2 administration.
lL-2 will start on the same day as cycle 2 and 3 of ipilimumab. ln general patients
can receive ipilimumab in the morning and be admitted in the afiernoon for lL-2
therapy the same day. lL-2 will begin after pre-medication and will be given as a
15 minute bolus intravenous infusion every I hours until a maximum of 14 doses
or unacceptable toxicity occurs according to institutional protocol for lL-2
administration.
Protocol \:ersiou Date: I I Auerlst l0I6: \,'ersrr:rr: "1.0

Pr-otocol: A Phnse Ii Sirrgle Ann Snrcly of High-Dose IL-l and Ipilirrrrruab rl Patieuts n,ith Uruesectable
Stage ill and Stase I\i lr{elanoura
Prurcipal Livestigator, f
lL-2 dosing is 600,000 l.U.lkg and will be based on baseline weight (in kilograms)
upon hospital admission for treatment. lL-2 will be held for toxicity as per
institutional guidelines. The total number of lL-2 doses should be recorded for
each cycle of treatment.
Special attention should be paid to the development of diarrhea in patients
treated with lL-2 since ipilimumab may also result in diarrhea. Since lL-2 diarrhea
is generally secretory and ipilimumab-related diarrhea is generally inflammatory
the assignment of causality may require stool analysis for white blood cells
and/or endoscopy with visualization of the colon mucosa with or without a biopsy.
A low threshold for diarrhea work-up and management should be used in this trial
. Follow-up (duration of study).
Subjects who are no longer receiving ipilimumab because of unacceptable
toxicity (refractory Grade > 3 irAEs) or due to investigator judgment are managed
in long term survival follow-up. Efficacy assessments for these subjects during
follow-up are as per the standard of care. Date of death is recorded. lf patient are
not able to come to clinic, then long term survival follow up will be conducted by
phone every 6 months.
Subjects who discontinue ipilimumab treatments should be followed until death or
the closure of the study (whichever is first),
- $ubjects who are no longer receiving ipilimumab because of clinical progression
and who have switched to alternative treatment are not followed formally except
to record the date of death.
4. SUBJECT SELEGTION CRITERIA
4.1 lnclusion Criteria
Willing and able to give written informed consent.
Histologic or cytologic diagnosis of cutaneous
unresectable (Stage lll) or metastatic (Stage lV).
is excluded.
Required values for initial laboratory tests:
. WBC
:20001uL
ANC 
r 1000luL
melanoma that is considered
Ocular and mucosal melanoma
1)
2)
3)
Protocol Versiol Date: I I .{usl*t l0l6: \,'er'rtorrt J.0

Protocol: A Phase II Single furr Snrdy of High-Dose IL-2 and Ipilirnrurrab iu Patients rsilh Urueseclable
Stage III a:rd Stage I\:lr.lelqqo1na
. Platelets 
:" 75 x 103/uL
. Hemoglobin i I g/dl (r 80 gll: may be transfused)
' Creatinine I2.0 x ULN
' ASTIALT 
L 2.5 x ULN for patients without liver metastasis,
": 5 times for patients with liver metastases
' Total Bilirubin <. 2.0 x ULN, (except patients with Gilbert's Syndrome, who
must have a total bilirubin less than 3.0 mg/dl)
No known active or chronic infection with HlV, Hepatitis B, or Hepatitis C. Testing
is not required unless clinically_suspected.
Performance status (ECOG 0-1; see Appendix for table).
Patients must have a life expectancy of greater than three months at the start of
the trial.
7) Patients must have a brain MRI or CT (with and without contrast) that is free of
active metastases. Metastases that have been treated with radiation or surgical
resection, are stable for at least 4 weeks and do not require steroids are eligible.
8) Patients may have received treatment of completely resected early stage
melanoma, cornprising interferon, radiation treatment, or experimental vaccine
therapy. and in the metastatic setting patient can have had treatment such as
chemotherapy, immunotherapy (except prior treatment with lpilimumab and lL-2),
and other experimental agent which was completed 4 weeks prior to enrollment.
9) Normal cardiac stress test for patients over 50 years of age.
10) Pulmonary Function: FEV1 and FVC > 65Yo of prediction for those patients with
extensive pulmonary metastases or chronic pulmonary disease history.
11) Men and women, i 18 years of age.
Women of childbearing potential (WOCBP) must be using an adequate method
of contraception to avoid pregnancy throughout the study and for up to 26 weeks
after the last dose of investigational product, in such a manner that the risk of
pregnancy is minimized. ln general. the decision for appropriate methods to
prevent pregnancy should be determined by drscussions between the
investigator and the study subject.
WOCBP include any female who has experienced menarche and who has not
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation,
Protocol \:ersion Date: I I Aueust l0I6: \:ersiou: ,1.0
4)
5)
6)
Page'12

Protocol: A Phase Il Single Anrr Snrdl'r:f High-Dose IL-l atd Iyrilirnr.unab in Pafierrts n'ith l-huesectable
Stage III antl Stage IV ]'.lelanoura
Priucipal Lrlestigator: f
) or is not postmenopausal. Post-menopause is
defined as:
' Amenorrhea a 12 consecutive months without another cause, or
' 
For women with irregular menstrual periods and taking hormone replacement
therapy (HRT), a documented serum follicle stimulating hormone (FSH) level
:'" 35 mlU/ml.
Women who are using oral contraceptives, olher hormonal contraceptives
(vaginal products, skin patches, or implanted or injectable products), or
mechanical products such as an intrauterine device or barrier methods
(diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing
abstinence or where therr partner is sterile (eg, vasectomy) should be considered
to be of childbearing potential.
WOCBP must have a negative serum or urine pregnancy test (minimum
sensitivity 25 lUlL or equivalent units of HCG) within 72 hours before the start of
ipilimumab.
Men of fathering potential must be using an adequate method of contraception to
avoid conception throughout the study [and for up to 26 weeks after the last dose
of investigational productl in such a manner that the risk of pregnancy is
minimized.
4.2 Exclusion Criteria
Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythrnia, or psychiatric illness/social situations that would limit
study compliance
Any other malignancy form which the patient has been disease-free for less
than 5 years, with the exception of adequately treated and cured basal or
squamo{Js cell skin cancer, superficial bladder cancer or carcinoma in situ of
the cervix.
Patients with primary ocular or mucosal melanoma are excluded-
Autoimmune disease. Patients with a history of inflammatory bowel disease,
including ulcerative colitis and Crohn's Diseasse, are excluded from this
study. as are patients with a history of symptomatic disease (eg. rheumatoid
arthritis, systemic progressive sclerosis [scleroderma], systemic lupus
erythematosus, autoimmune vasculitis [eg, Wegener's Granulomatosisl);
motor neuropathy considered of autoimmune origin (e.9. Guillain-Barre
Syndrome and Myasthenia Gravis).
1)
2)
3)
4)

Plotocol: A Phase II Single Arru Snrcll. of High-Dose IL-l zurd lpilirnrurrab in Patienrs wilh Urueseoable
Stage III and Staee IV \Ielauonra
I
5) Any underlying medical or psychiatric condition, which in the opinion of the
investigator will make the administration of ipilimumab hazardous or obscure
the interpretation of AEs, such as a condition associated with frequent
diarrhea.
6) Patients with underlying heart conditions who are deemed ineligible for
surgery by cardiology consult. Patients with reversible ischemic changes on
cardiac stress test.
7) Any non-oncology vaccine therapy used for prevention of rnfectious diseases
{for up to 1 month before or after any dose of ipilimurnab).
8) A history of prior treatment with lL-2, ipilimumab or prior CTLA4 inhibitor or
agonist for metastatic disease. Prior therapy with ipilimumab in the adjuvant
setting is allowed provided there were no Grade 3 or greater adverse events
that did not resolve with limited corticosteroid use, and more than 6 months
have elapsed since final adjuvant treatment and start of study treatment on
this protocol.
9) Concomitant therapy with any of the following: interferon, or other non-study
immunotherapy regimens: cytotoxic chemotherapy; immunosuppressive
agents: other investigation therapies: or chronic use of systemic
corticosteroids. lmmunosuppressive agents should be stopped within 4
weeks of randomization. $teroids should be stopped 14 days prior to
beginning ipilimumab therapy.
10)Women of childbearing potential (WOCBP), defined above in Section4.1,
who:
a. are unwilling or unable to use an acceptable method of contraception to
avoid pregnancy for their entire study period and for at least I weeks after
cessation oi study drug, or
b. have a positive pregnancy test at baseline, or
c. are pregnant or breastfeeding.
1 1) Prisoners or subjects who are compulsorily detained (involuntarily
incarcerated) for treatment of either a psychiatric or physical (eg, infectious)
illness.
4.3 Data Safety Monitoring Plan
The Rutgers Cancer lnstitute of New Jersey has established a Data and Safety
Monitoring Plan (DSMP) for the conduct of clinical trials in patients with cancer^ A
dedicated Data Safety Monitoring Committee (DSMC) will serve as the data safety
monitoring board for this clinical trial. All unexpected and serious adverse events will be
Protocol \ier;ion Date: l l Aueust 1016: \.'ersron: 4.0

Protocol: A Phase Ii Silgle A"un Sttrcly of HiSh-Dose IL-l alrl ipilruuuuatr in pafierrrs q.irh Llru.esectable
Stage III arrd Staee I\'lUrlanorla
Pnncipal hn'estigator, f
reported to the DSMC (as well as each institutional IRB and study sponsor) according to
the reporting requirernents detailed in Section 8.0 of this protocol and per tnu I
fosMP. 
An independent DSMB will also be established composed of all study
site principal investigators, two independent physicians familiar with tumor
immunotherapy clinical trials and one biostatistician for external review of the safety
data. An interim safety analysis will be conducted after the first 6 patients are enrolled.
The independent DSMB will review the safety data and if concerns are found, the
independent DSMB may recommend that the ipilimumab dose be reduced to 3 mg/kg.
5. DRUG ADMINISTRATION GUIDELINES
5.1 lpilimumab
Each patient will receive ipilimumab at '10 mg/kg by intravenous infusion. lnfusions
should be given over g0 minutes (not bolus or lV push).
Dose Calculations
Calculate Total Dose as follows:
Patient body weight in kg x 10 mg = total dose in mg
Calculate Total lnfusion Volume as follows:
Totaldose in mg + 5 mg/ml = infusion volume in mL
Calculate Rate of lnfusion as follows:
lnfusion volume in mL + 90 minutes = rate of infusion in mumin.
For example, a patient weighing 114 kg (250 Ib) would be administered 1140 mg of
ipilimumab (114 kg x 10 mg/kg = 1140 mg) with an infusion votume ot 2Zg mL (1140 mg
+ 5 mg/rnl = 228 mL) at a rate of approximately 2.5 ml/min (228 mL + g0 minutes) in g0
minutes. All calculations should be based on screening weight. As long as any weight
changes are lAo/o or less from screening weight, further dosing can be based on the
screening weight.
5.1.1 Storage, Preparation, and Administration
lpilimumab lnjection. 50 mg/vial (5 mg/ml) or 200 mg/vial (5 mg/ml), must be stored
refrigerated (2"C to 8'C) and protected from light. ln preparation of infusion, ipilimumab
rnay be stored in lV infusion bags (PVC, non-PVC/non-DEHP) or glass infusion
containers at room temperature or refrigerated (2oC - 8oC) for up to 24 hours. Drug must
Airgust l0l6: \:ersron: .1.0

Protocol: A Phase II Single A.rtr Stucly of High-Dose IL-? and Ipilirnumab iu Pafienrr Lr,irh Llru'esectable
Stase III and Staee I\' ltlelanoura
rrrrrLrrr.rr rrr\E\rrE.rrrrr I
be completely delivered to the subject within 24 hours of preparation. This includes any
time in transit plus the total time for the infusion.
As with all injectable drugs, care should be taken when handling and preparing
ipilimumab. Whenever possible, it should be prepared in a larninar flow hood or safety
cabinet using standard precautions for the safe handling of intravenous agents, applying
aseptic technique. Latex gloves are required. lf ipilimumab concentrate or solution
comes in contact with skin or mucosa, immediately and thoroughly wash with soap and
water.
After final drug reconciliation, unused ipilimumab solution should be disposed of at the
site following procedures for the disposal of anticancer drugs.
5.1.2 Preparation and Adrninistration Guidelines
The supplies needed for ipilimumab preparation and administration include calibrated
syringes and infusion containers. lpilimumab is to be administered as an lV infusion
using a volumetric pump through a 0.2 or 1.2 micrometer in-line filter (supplied by site) at
the 10 mg/kg dose (or placebo equivalent). See the current lnvestigator Brochure for
additional information on allowable filter types. The infusion must be completed in g0
minutes with a 10 ml normal saline flush at the end. The ratio and rate will be specified in
the pharmacy manual. The total dose must be calculated using the most recent subject
weight (obtained within 3 days of the dosing visit, and prior to the infusion).
As ipilimumab is stored at refrigerated temperatures (2-8oC), allow the appropriate
nurnber of vials of ipilimumab to stand at room temperature for approximately five
minutes.
Aseptically withdraw the required volume of ipilimumab solution into a syringe. lnsert the
needle at an angle into the ipilimumab vial by placing the needle - bevel side down -
against the glass, with the tip touching the neck of the vial. The initial solution
concentration is 5 mg/ml [Note: A sufficient excess of ipilimumab is incorporated into
each vial to account for withdrawal lossesl.
Ensure that the ipilimumab solution is clear colorless, essentially free from particulate
matter on visual inspection. lf multiple vials are needed for a subject, it is important to
use a separate sterile syringe and needle for each vial to prevent problems such as
dulling of needle tip, stopper coring, repeated friction of plunger against syringe
barrelwall, etc.
lnject ipilimumab solution withdrawn into an appropriate size evacuated infusion bag to
produce a final infusion volume that has been calculated from
Protocol Version Date: I I .{ueust 1016: \:ersion: 4.0

Protocol: A Plmse II Single Arrr study of High-Dose IL-l and Ipilirnumab iu Patielrts rvith Urueseclable
Stase III and Stase I\']vlelarrorna
rt l'(tual rra...,rro,rr. f
patient. For example, if preparing a l0mglkg treatment for a 55 kg patient you will
use over 3 vials (or 650 mg), the drug solution volume will be 10 mL per vial or 130
mL total.
lf the totat dose calculates to less than 90 mL of solution then the total dose needed
should be diluted to a total volurne of 90 mL in 0.9% sodium chloride.
Mix by GENTLY inverting severaltimes. DO NOT shake.
Visually inspect the final solulion. lf the initial diluted solution or ftnal dilution for infusion
is not clear or contents appear to contain precipitate, the solution should be
discarded.
Do not draw into each vial more than once. Any partial vials should be safely discarded
and should not be stored for reuse.
lpilimumab should be administered under the supervision of a physician experienced in
the use of intravenous (lV) agents. lpilimumab is administered as an lV infusion only.
5.1.3 DoseModifications
Dose de-escalation of lL-2 from 600,000 lU/kg or ipilimurnab from 10 mg/kg is not
allowed.
5.1.3.a lpilimumab Dose Delay Rule
Decisions to skip an ipilimumab dose must be made on specified safety criteria.
Treatment with ipilimumab will be skipped or discontinued if the subject experiences at
least one adverse event, specified below, considered by the investigator to be
"possibly", probably" or "certainly" related to ipilimumab treatment. The
investigator should contact the study Pl and/or BMS for any adverse event that will
prompt a skipped dose or discontinuation of ipilimumab.
The following criteria will be used to deterrnine dose skipping, restarting doses, or
discontinuing ipilimumab. Patients who require steroids must be discussed with the
medical monitor of the trial prior to retreating with ipilimumab.
It may be necessary to skip study drug dosing for the following related adverse
event{s}:
. Any > Grade 2 non-skin related adverse event (including irAEs), except for laboratory
abnormalities Any: Grade 3 laboratory abnormality
Protocol Ver:ion Date: ll Aueust l0l6: \''ersiou: 4.0

Protocol: A Pluse II Single fulr Snrcly' of High-Dose IL-3 and Ipililuurmb it Parieurs u,irh Ltueseuable
Stage III and Stage IV N.Ielauoua
Principal Irrr'.stigutor: f
' 
Any adverse event, laboratory abnormality or intercurrent illness that, in the judgment
of the investigator, presents a substantial clinical risk to the subject with continued
dosing.
It-is__leSesgl1r_to_sklp"s"_tudy_drsq_dqs&slslthe le_[gudns -q_dygrss syerl]!$
' 
Any > Grade 3 skin related adverse event regardless of causality, unless reversible
within 3 weeks.
Restart lplllmumab dosing if/when the adverse eventts) resolve(s) to
S Grade 1 severity or returns to baseline within 2 weeks of initial dose
administration:
. lf the adverse event has resolved. restart ipilimumab dosing at the next scheduled
timepoint per protocol.
. lf the adverse event has not resolved in the protocol-specified dosing window (3
weeks [t3 days], the next scheduled dose will be skipped and dosing will be
resumed at the subsequently scheduled dose.
. lf > 1 dose is expected to be skipped, the dosing schedule modifications must be
discussed with the principal investigator prior to implernentation.
5.1.4 Discontinuation of Study Therapy
It is possible that either lL-2 or ipilimumab may need to be discontinued for specific drug-
related toxicity in a given cycle. Any decision to discontinue a drug should be made in
consultation with the medical monitor for the study. General guidelines are provided
below.
Subjects MUST be discontinued from sludy therapy AND withdrawn from the study for
the following reasons:
. Withdrawal of informed consent (subject's decision to withdraw for any reason)
. The occurrence of any grade 4 adverse event related to lL-2 that does not decrease
to grade 1 within 4 weeks of completing lL-2 therapy
. Any clinical adverse event, laboratory abnormality or intercurrent illness which, in the
opinion of the investigator, indicates that continued treatment with study therapy is
not in the best interest of the subject
Plotocol Versiou Date; I I $.ueust 3{)16: \'ersiou: "1,0
Page .18

Protocol: A Phase II Single A:ru Snrdy of High-Dose IL-? ald lpilirnr"unab il Parients u'irh Uru.eseoable
Stage III and Stage IV \{elalotna
Pnncipal Lr..".tig*tor, f
. Pregnancy
All WOCBP should be instructed to contact the investigator immediately if they
suspect they might be pregnant (e.9., missed or late menstrual period) at any
time during study participation. lnstitutional policy and local regulations should
determine the frequency of on study pregnancy tests for WOCBP enrolled in the
study.
The investigator must immediately notify BMS in the event of a confirmed
pregnancy in a patient participating in the study.
. Termination of the study by
' 
lmprisonment or the compulsory detention for treatment of either a psychiatric or
physical (e.9.. infectious disease) illness.
5.1.5 Permanent Discontinuation of lpilimumab
5.1.5.a Permanent Discontinuation for Related Adverse Events
The following treatment related non-neurotogical adverse events require
permanent discontlnuatlon of ipilimumab:
' 
Any z Grade 2 eye pain or reduction of visual acuity that does not respond to topical
therapy and does not improve to s Grade 1 severity within 2 weeks of starting
therapy, OR, requires systemic treatment.
. Any ) Grade 3 bronchospasm or other hypersensitivig reaction.
' 
Any other > Grade 3 non-skin related adverse event with the exception of events
listed under "No Discontinuation" (below).
' 
Any > Grade 4 laboratory abnormalities. except AST, ALT, or Total Bilirubin
. ASToTALT>8xULN
. Total Bilirubin > 5 x ULN
. Any other > Grade 4 adverse event
' Any adverse event, laboratory abnormality or intercurrent illness which, in the
judgment of the investigator, presents a substantial clinical risk to the patient with
continued dosing.
' The development of progression (irPD) in the global tumor burden confirmed by
serial imagrng 4-6 weeks later andlor clinical deterioration of subject's condition such
that further beneflt from ipilimumab dosing is unlikely or requires a change of
therapy.
Please refer to the lB for specific treatment alEorithms.
The following neurological adverse event requires permanent discontinuation of
ipilimumab and defines unacceptable neurotoxicity:
. Any motor neurologic toxicity >/= Grade 3 regardless of causaliU _
Protocol Version Date: I I Aueust lfjI6: \'ersiol: 1.0

Protocol: A Phase II Single tum Snrdy of High-Dose IL-l ald Iliilimumal.r in Patieuts rl.ith Lhueseqtable
Staee III aud Stase [\: \lelauorua
I
. Any>/= Grade 3 treatment related sensory neurologic toxicity
Please refer to the lB for specific treatment algorithms.
5.1.5.b Exceptions to Permanent Discontinuation
. Potentially reversible inflammation (< Grade 4), attributable to a local anti-tumor
reaction and a potential therapeutic response. This includes inflammatory reactions
at sites of tumor resections or in draining lymph nodes, or at sites suspicious for, but
not diagnostic of metastasis.
. Hospitalization for 5 Grade 2 adverse events where the primary reason for
hospitalization is to expedite the clinrcalwork-up.
. Patients with the following conditions where in the investigator's opinion continuing
study drug administration is justrfied.
; 
Ocular toxicity that has responded to topical therapy.
- Endocrinopathies where clinical symptoms are controlled with appropriate
hormone replacement therapy.
- Note: lpilimumab may not be restarted while the patient is being treated with
systemic corticosteroids except for patients on stable doses of hormone
replacement therapy such as hydrocortisone.
5.1.6 lmmune-Related Adverse Events (irAEs): Definition, Monitoring, and
Treatment
Blocking CTLA4 function may permit the emergence of auto-reactive T cells and
resultant clinical autoimmunity. Rash/vitiligo, diarrhea/colitis, uveitis/episcleritis, hepatitis,
and hypopituitarism were drug-related, presumptive autoimmune events, now termed
irAEs, noted in previous ipilimumab studies.
For the purposes of this study. an irAE is defined as an AE of unknown etiology
associated with drug exposure and consistent with an immune phenomenon. Efforts
should be made to rule out neoplastic, infectious, metabolic, toxin or other etiologic
causes prior to labeling an AE an irAE. Serological, immunological, and histological
(biopsy) data should be used to support the diaEnosis of an immune-mediated toxicity.
Suspected irAEs must be documented on an AE or SAE form.
Patients should be informed of and carefully monitored for evidence of clinically
significant systemic irAE (e.9., systemic lupus erythematosus-like diseases) or organ
specific irAE (e.9., rash, colitis, uveitis, hepatitis or thyroid disease). lf an irAE is noted,
Plotocol \:ersiorr Dale: I I Aueust l0l6: Yersrori: 4.0
Page 50

Protocol: A Phase II Single .fum Stucly of High-Dose IL-3 and Ipilinruuab in Patieuts rvith Lirx'e.ser--table
Staee III arrd Staee I\']rlelarrorua
rtI'clual rrr. 
"",ro,,.,au. f
appropriate work-up (including biopsy if possible) should be performed, and steroid
therapy may be considered if clinically necessary. .
It is unknown if systemic corticosteroid therapy has an attenuating effect on ipitimumab
activity. However, clinical anti{umor responses have been maintained in patients treated
with corticosteroids and discontinued from ipilimumab. lf utilized, corticosteroid therapy
should be individualized for each patient. Prior experience suggests that colitis
manifested as > Grade 3 diarrhea requires corticosteroid treatment..
Specific treatment algorithms for immune-related adverse events are included as
appendices in the lB.
5.1.7 Other Guidance
5.1.7.a Treatment of lnfusion Reactions A$sociated with lpilimumab
Since ipilimumab contains only human protein sequences, it is less likely that any
allergic reaction will be seen in patients. However, it is possible that infusion of
ipilimumab will induce a cytokine release syndrome that could be evidenced by fever,
chills, rigors, rash, pruritus, hypotension. hypertension, bronchospasrn, or other
symptoms. No prophylactic premedication will be given unless indicated by previous
experience in an individual patient. Reactions should be treated based upon the
following recommendations.
. For mild symptoms (e.9., localized cutaneous reactions such as mild pruritus,
flushing, rash):
- Decrease the rate of infusion until recovery from symptoms, remain at bedside
and monitor patient.
- Complete the ipilimumab intusion at the initial planned rate.
- Diphenhydramine 50 mg lV may be administered at the discretion of the treating
physician and patients may receive additional doses with close monitoring.
- Premedication with diphenhydramine may be given at the discretion of the
investigator for subsequent doses of ipilimumab.
. For moderate symptoms (any symptom not listed above [mild symptomsJ or below
[severe symptoms] such as generalized pruritus. flushing, rash, dyspnea,
hypotension with systolic BP >80 mmHg):
- lnterruptipilimumab.
- Administer diphenhydramine 50 mg lV.
- Monitor patient closely until resolution of syrnptoms.
Protocol Ver*ior Date: I I Aueust l0l6: \:ersiorr: ,1.0

Protocol: A Plmse II Single .furtr Stnrty of High-Dose IL-3 ald Ipilinumab il Patienti r'r'ith Uru'esectable
Stase III and Staee IV lr{elaloura
Pnncipal Lr.'estigator, f
- Corticosteroids may abrogate any beneficial immunologic efiect, but may be
administered at the discretion of the treating physician.
- Resume ipilimumab infusion after recovery of symptoms.
- At the discretion of the treating physician, ipilimumab rntusion may-be resumed at
one half the initial infusion rate, then rncreased incrernentally to the initialinfusion
rate.
- lf symptoms develop after resumption of the infusion, the infusion should be
discontinued and no additional ipilimumab should be administered that day.
- The next dose of ipilimumab will be administered at its next scheduled time and
may be given with pre-medication (diphenhydramine and acetaminophen) and
careful monitoring, following the same treatment guidelines outlined above.
- At the discretion of the treating physician additional oral or lV antihistamine may
be administered prior to dosing with ipilimumab.
' For severe symptoms (e.g., any reaction such as bronchospasm, generalized
urticaria, systolic blood pressure <80 mm Hg, or angioedema):
- lmmediately discontinue infusion of ipilimumab, and disconnect infusion tubing
from the sub.iect.
- Consider bronchodilators, epinephrine 1 mg lV or subcutaneously, and/or
diphenhydramine 50 mg lV, with solumedrol 100 mg lV, as needed-
- Patients should be monitored until the investigator is comfortable that the
symptoms will not recur.
- No further ipilimumab will be administered.
. ln case of late-occurring hypersensitivity symptoms (e.9., appearance within one
week after treatrnent of a localized or generalized pruritus), symptomatic treatment
may be given (e.9., oral antihistamine, or corticosteroids).
5.1.7.b Treatment of lpilimumab-Related lsolated Drug Fever
ln the event of isolated drug fever, the investigator must use clinical judgment to
determine if the fever is related to the ipilimumab or to an infectious etiology. lf a patient
experiences isolated drug fever, for the next dose, pre{reatment with acetaminophen or
non-steroidal anti-inflammatory agent (investigator discretion) should be instituted and a
repeated antipyretic dose at 6 and 12 hours after ipilimumab infusion, should be
administered. The infusion rate will remain unchanged for future doses. lf a patient
experiences recurrent isolated drug fever following premedication and post dosing with
an appropriate antipyretic. the infusion rate for subsequent dosing should be decreased
P'otoc.l \:ersio, Date: I I Atlellst 1016: \'ersion: -1.0 
I 
I
I
Page 51

Protocol: A Phase 11 Single turn snrcly of High-Dore ll.-l ald lpilimrnmb il PatieuB r'r'ith Lhuesectable
Staee III aud Stase IV lvlelattorua
Principal hn'estigator, f
to 500/o of the previous rate. lf fever recurs following infusion rate change, the
investigator should assess the patient's level of discomfort with the event and use
clinical judgment to determine if the patient should receive further ipilimumab.
5.1.7.c Liver Function Tests (LFT) Assessments Required Prior to
Administration of iPilimumab
Liver function tests (AST, ALT, T. bilirubin) witl be evaluated for every subject prior to
administration of ipilimumab. Blood samples must be collected and analyzed at local or
central labs within 3 days prior to dosing. LFT results must be reviewed by the principal
investigator (or designee) to meet dosing criteria specifications: ':: 2.5 x ULN for AST,
ALT and " 2.A x ULN for T^ bilirubin unless liver metastases are present in which case
LFT"n 5 x ULN for AST, ALT and T. bilirubin r 3.0 x ULN) prior to dosing.
lf, during the course of treatment abnormal LFT values are detected, the subject must be
managed using the hepatotoxicity algorithm section of the ipilimurnab lnvestigators.
5.2 lnterleukin-2 (lL-2; Aldesleukin; Proleukin)
lL-2 will be given intravenously (lV) in a dose of 600,000 lU/kg every eight hours for up
to 14 doses in each cycle. Cycles of lL-2 will be repeated in 3 weeks with the next dose
of ipilimumab.
P*oseCalculelisnE_pj-lL*-2
Calculate Total Dose as follows: Patient body weight in kg X [600.000 MIU] = total dose
in MIU
Calculate Rate of lnfusion as follows: lnfusion volume in ml * 15 minutes=rate of infusion
in ml/min
5.2.1 Storage, Preparation, and Administration of lL-2
Reconstituted lL-2 should be further diluted with 5olo Dextrose, USP. Do not mix with
saline containing solutions. Reconstituted lL-2 may be diluted as necessary in volumes
of 50 mt to 500 ml with SYo Dextrose, U$P. When diluted for lV administration in 590
Dextrose lnjection, USP, in a plastic bag (e.g. Viaflex, manufactured by Travenol
Laboratories, lnc.,) lL-2 is chemically stable tor 48 hours at refrigerated and room
temperatures, 2-30.'C. lntact vials are stored in the refrigerator (2-8'C) protected from
light. Each vial bears an expiration date.
Protocol Versiort Date: I I Arrel*t lfll6: \:ersrou: 4.f)

Protocol: A Phase II Single fun snrdy of High-Dose IL-? and Ipilirmuuab rn Patienis rl'ith Linreseclable
Srase III arrd Stage [\' Nlelartorna
rl lll.lLill lll\ tr't tg{r't. I
5.2.2 lL-2 Formulation/Reconstitution: lL-2 (Aldesleukin*)
Forrnulation/Reconstitution: lL-2 (Aldesleukin,&), please see the lnvestigators Brochure
for the complete pharmaceutical package insert) is a commercially available product
(Prometheus).
1)The medication is provided as a lyophilized powder and a vial of medication is
reconstituted with 'l"2mg of Sterile Water for lnjection, USP, and the resultant
concentration is 18 million lU/ml.
2)Diluent should be directed against the side of the vile to avoid excess foaming.
Swirl contents gently until completely resolved.
3)Do not shake.
Since vials contain no preservative, reconstituted solution should be used within 8 hours.
5.2.3 Dose Modifications of lL-2
No dose modifications will be allowed. However, based on principle investigator's
discretion, dose can be calculated using the ideal body weight. lf DLT occurs, dose
delays will be administered according to investigators judgment. When DLT has
resolved, the patient may be continued at the same dose of lL-2 or may be withdrawn
from treatment with lL-2.
For lL-2, serious adverse events are defined as any of the following:
. Any grade 3 or greater non-hematological toxicity, with the exceptions of grade 3
arthralgia/myalgias and brief (less than 1 week)grade 3 fatigue.
. Hypotension with systolic BP<80 and not responsive to fluid resuscitation or
va$opressors
. 
Pulmonary edema requiring treatment with Lasix.
. Any cardiac arrhythmia or sinus tachycardia> 130 bpm
. Severe altered mental status
. 
Elevation of creatinine (>4 .0 mgldl, hold dose, >8 mg1dl, stop treatment)
' 
Elevated total bilirubin (>3.7 mg/dl, consider holding dose. 7.5 mgldl, consider
stopping therapy)
. Low platelet count (<75 k/ul, hold dose, <50 ldul, consider stopping therapy)
Protocol \:ersion Date: I I Aue.ust 3016: \iersrorrt J.0

Protocol: A Phase II Single fun Str.rdy of High-Dose IL-? atd Ipilimrunab il Patierrls u'ith Liru'esectable
Staee III aud Stase I\'lrlelarrorua
I
Common and expected toxicities related to lL-Z administration will not be considered
reportable adverse events except for autoimmune events or the treating clinrcal
investigator believes that ipilimumab contributed to the development of the adverse
event.
ln the event that a patient is experiencing a significant ipilimumab-related adverse event
at the time that lL-2 is scheduled, the lL-2 may be held until the ipilimumab-related
adverse event resolves. lL-2 may be given at the next regularly scheduled 3 week cycle.
ln general, if the following ipilimumab-related adverse events are present at the time of a
scheduled lL-2 treatment, the lL-Z should be held:
Any l Grade 2 non-skin related adverse event (including irAEs), except for laboratory
abnormalities
Any ) Grade 3 laboratory abnormality
Any adverse event, laboratory abnormality or intercurrent illness that, in the judgment
of the investigator, presents a substantial clinical risk to the subject with continued
dosing.
lf these adverse events resolve to Grade 1 or less within three weeks, lL-2 can be given
at the next regularly scheduled cycle of treatment. lf there are questions about a speciflc
patient, the investigator may contact the study Pl andlor BMS for further discussion.
5.?.4 Definitions of lL-2 Dose-Limiting Toxicity
Toxicity will be evaluated according to the NCI Common Toxicity Criteria, CTCAE v4.0.
Common and expected toxicities related to HD lL-2 administration will not be considered
reportable adverse eventg unless ipilimumab contributed to the development of the
adverse event in the judgment of the treating clinician. lL-2 related side effects are vary
in incidence and intensity mainly as results of capillary leak syndrome (CLS), the
leakage of intravascular fluid to the extra vascular space, subcutaneous tissue or alveoli
[781. CLS causes hypotension, pulmonary and peripheral edema, significant weight gain,
altered mental status. tachycardia and oliguria. These symptoms usually resolve within
24-48 hours of following treatment cessation with an exception of fatigue which can
persist for 5-7 days post discharge.
1L-2 will be permanently discontinued for any grade a
hematological adverse events that do not resolve to
Protocol \,'ersiou Date: I I .{usust l0l6: \:ersron: ,1.0
4
s
hematological or ) 3 non-
grade

Prntocol: A Phase II Sitgle Arrr stucly of High-Dose IL-3 ald ipilinuurrab irt Parientr rl,ith Uruesectable
Staee III and Staee IY Nlelarrorua
rtI,LlIJ.t 
tll\ E5,gdtL,. I
cornpleting lL-2 treatment if the side effect is definitely related to lL-2. This will be
considered a DLT and the patient will be removed from the study.
5.3 Prohibited and Restricted Therapies During the Study
5.3.1 Prohibited Therapies
Patients in thrs study may not use vaccines for the treatment of cancer or prevention of
disease unless indicated as a component of the protocol regimen (including those for
common medical conditions) for up to one month pre and post dosing with ipilirnumab.
Concomitant systemic or local anti-cancer medications or treatments are prohibited in
this study while receiving ipilimumab treatments.
Patients may not use any of the following therapies during the study.
. Any non-study anti-cancer agent (investigational or non-investigational)
. Any other investigational agents
' 
Any other (non-CA184024 related) CTLA4 inhibitors or agonists
. lmmunosuppressiveagents
, Chronicsystemiccotticosteroids
. Any non-oncology vaccine therapies used for the prevention of infectious diseases
(for up to 30 days prior to or after any dose of study drug).
5.3.2 Restricted Therapies
Patients should avoid beta-blockers while on this protocol since these agents may
preclude successful treatment of ll-2-related hypotension. Patients may be weaned off
of beta-blockers two weeks prior to study enrollment under the supervision of their
primary cardiologist.
5.3.3 Precautions
Caution is advised when treating patients with high-dose lL-2 who have previously been
administered ipilimumab. particularly in patients who experienced ipilimumab-related
diarrhea/colitis. Colonoscopy or sigmoidoscopy with biopsy may be advisable in these
patients
prior 
to
tL-2
administration.
Protocol Versiou Date: I I Auell.it 1016: \:ersiori: 4.0

Protocol; A Phase II Single Ar:rr Shrdy of High-Dose IL-l and Ipiliurturrab in Palients rvith Llru'ese$able Stase
III and Staee IV \lelanorrra
Principal Iir'.rtigotor, f
6. STUDY PROCEDURES AND OBSERVATIONS
6.1 Time and Events Schedule
All patients must give written consent to participate in the study. A total of 11 visits are
planned including one pre-visit. up to eight treatment visits and 4 followup visits at 6, 9. 12
and 24 months. Time and events schedule is summarized in Table 5.
Table 5: Time and events schedule for the protocol
'rocedure
Screening
lnduction
lnduction
Assessment
Maintenance
End of
Treatment
L
Weeks (:.1)':
Pre-Treatment
Tx't
Tx2
Tx3
Tx4
FIU 1
Tx5
FIU 2
Tx6
F/U 3
Tx7
FIU4
TxB
FIUs
FIU 6
.)
1
4
a
10
12
24
36
48
60
144
Months
1
?
6
r.l
12
24
JO
Eligibility
Assessments
nformed Consent
X
nclusion/Exclusion
lriteria
X
X
MedicalHistory
X
X
X
X
X
X
X
$afety Assessments
)hysical Examination
X
X
X
X
X
X
Iargeted Physica
Ixam
X
X
X
X
=COG Performanc€
Status
X
X
X
X
X
X
X
X
x
/ital Signs (including
reioht and weioht)b
X
X
X
X
X
X
X
X
X
X
x
\dverse Events
\ssessmenUCon Meds
X
x
X
X
X
X
X
X
X
-aboratory Testsl
X
X
X
X
X
X
X
Jrinalysis
X
X
x
)regnancy Test?
X
X
X
X
X
x
X
X
KG
X
x
s
lardiac Stress Test
rulmonary Functior
l'est(if needed)7
X
ifficacy
Issessments
Protocol Versiou Date: ?9 Julv l0l5 Verrion: -1.0
I
Fage iT

Prntocol: A Phase II Single.{mt Strrdl, of High-Dose IL-? ancl Ipilinruriab i1 Patiells with Llruesectatrle Stage
III and Stae,e IV Nlelanoma
Abbreviations: FlU. follov/-up: lL2. interleukin-2: lpi. ipilumimab: Tx. treatment visit
apre-trealmeni imaging. informed consent. H&P. cardlac stress test. pulmonary functions studies(if needed).
concomitant medications and tumor biopsy must be completed within 4 weeks of stafiing treatment. vital signs, routine
labs, EKG must be completed within 2 weeks of starting treatment. Pregnancy testing, if needed. must be done within
72 hours of sta$ng treatment. Follow-up imaging must be done r'"'ithin 1 week of scheduled follow-up visit.
r,Vital signs should include temperature. heart rate, respirations, blood pressure, height and weight at each visit.
rRoutine lab tests include cbc v/ith differential. serum electrolytes, BUN creatinine, glucose. hepatic function studies
{bilirubin, AST. ALT). LDH. . T3, T4 and TSH prior to treatment:;
ra pre- lL-2 standard tests: Urinalysis and EKG prior to lL-2. Patients rnust also have institutionally mandated pre-lL-2
studies. such as cardiac stress test. pulmonary function studies.
:pregnancy test must be done in all women of reproductive polential and subjects should be counseled in avoiding
pregiancy'Ouring treatment as outlined in Section 4. For woman of child-bearing potential. a negative resull must be
confrrmed within 24 hours of each dose of ipilimurnab. The lest should be repeated at week 24 in pre-menopausal
women prior to beginning maintenance ipilimumab treatrnent. Women under tfle age of 62 must have a documented serum
follicle slimulating homrone, (FSH) level > 40mlU/ml
rPatients should have a CT scan of the chest, abdomen and pelvis with and r,vithout contrast and CT or MRI of the
brain rvithin 4 v/eeks of starting treatrnent and during eflicacy assessment ',veeks. Additional imaging may be done at
th€ investigators discretion to better evaluate disease (e.g CTIMRI of the lower extremity for soft lissue disease. PET
or bone scan for borderline lesions).
{peripheral blood will be collecled for immune analysis at the indicated time points. This will include 4 green or red
CPT iubes and 2 red top tubes. Blood will be shipped to the central immunology lab as described in Section 1 2. 1 .
sln consenting patients wilh easlly accessible disease a tumor biopsy will be Performed at the indicated time points. An
incisional. exiilionat or core ne6dle biopsy is acceptable. Tissue should be sent to the central immunology lab as
described in Section '12.1.. Biopsy is optional and archival tissue is acceptable for the pre-treatment sarnple.
6 Long term survival follow up will be conducted by phone if patient is unable to come to clinic.
7 pulmonary Function: FEV1 and FVC > 55o/o of prediction for those patients wilh extensive pulmonary metastases or
chronic pulmonary disease history.
Prilcipal Inve"stigator:
\ssessmenl 1 (safety)
x
X
X
X
X
X
X
X
X
X
X
\ssessment 2
lmaoino) (efficacv)3
A
X
X
X
X
X
\ssessment 3
lmmunoloqv)a
X
X
X
x
A
X
X
X
ltssue
)ollection (optional )s
X
v
\
Study Treatment
ra
L-1
X
(
(
Protocol Yersiort Date: 39 July 2015 \:errion: i.0

Protocol: A Plrase II Single .tu:tr Snrdl'of High-Dose IL-i and Ipiliruunrab in Patients u'ith thu'erectalile Stage
III and Staee I\r \lelanoma
Principal Iu.'.rrigotor, f
6.2 Procedures by Visit
The Time and Events Schedule summarizes the frequency and timing of various
measurements.
6.2.1 Study Procedures by Visit and Treatment Cycle
Note that results of all safety laboratory tests (that is, all chemistry and all hematology
results) must be obtained and reviewed before ipilimumab administration, as applicable. All
laboratory results must be within the established range before ipilimumab is administered.
AII induction period laboratory samples must be collected within a window of up to 7 days
before administration of ipilimumab. Laboratory evaluations using a local laboratory must be
performed and the result examined by the investigator before administration of each dose of
ipilimumab.
6.2.2 Screening/Baseline Visit
Once informed consent has been obtained, the tests described in Table 6 will be pefformed.
All tests must be conducted within two weeks prior to starting treatment, with the exception
of CT scans of the, chesV abdomenl pelvis areas and CT or MRI of the Brain, which may be
done up to four weeks before the first treatment. After giving fully informed consent, patients
will be subjected to a medical history and physical examination to document general fitness
to proceed with the trial. The diagnosis should be confirmed histologically from the patient's
record. Peripheral blood will be drawn and shipped to the tumor immunology lab for a
baseline sample, and shipped to the central tumor immunology lab as described in Section
12.1. lf possible, and the patient consents, biopsy samples preferably will be taken and sent
to the tumor immunology laboratory as described in Section 12.1. Samples will be assessed
at baseline, during and post-treatment periods. Metastases will be documented using
relevant CT scans (chest, abdomen, and pelvis wMout contrast). An MRI scan of the brain
will be obtained. A cardiac stress test and pulmonary function tests will be obtained in
appropriate patients before lL-2 as per institutional guidelines.
Table 6: Pretreatment evaluations for all groups
Medical History
)hysical Exam
s4 rveeks
: 
Cardiac Stress Test
- Pulmonary Function Test. (optional)
- Medical History including
: ConcomitantMedications Physical Examination
)iagnostic imaging
<4 rveeks
, Brain MRI or CT
:-,CT scan (chest abdomen and pelvis w/wout coryq$)
Protocol \:ersion Date: l!) Jrrlv ?015 \IErricrn: -i.{J

Principal hr.,'estieator
lnclusion/exclusion
:riteria, Medica
History. anc
Physical
Examination.
s2 v;eeks
: 
Height
: Weight
: 
Blood, pressure (sitting) / pulse (resting)
: ECOG performance status
] 
EKG
Serum pregnancy. (i
apolicable)
<72 hours
-ICG
rlematology
s2 weeks
: 
Complete Blood Count (CBC),
: 
Differential, Platelets
3iochemistry
s2',areeks
f 
Electrolytes (sodium, potassium, calciurn, chloride
and magnesium),
: Alanine aminotransferase (ALT) andlor aspartate
Aminotransferase (AST),
: Alkaline phosphatase (ALP),
: Total bilirubin,
: 
Serum creatinine,
': Blood urea nitrogen (BUN),
: Serum protein,
: Albumin,
- Lactic dehydrogenase (LDH),
: 
T3,
- T4,
: Thyroid stimulating hormone (TSH)
Jrinalysis
s2 weeks
- Protein,
: WBC,
: RBC, Glucose
fumor 
biopsl
ioptional)'
s2 weeks
mmunohistochemistry, confocal microscopic study anc
immunophenotypes of T subsets
mmunohistochemistry and confocal microscopy analysis
of tumor microenvironment
munologic
>nltoring
<2 weeks
mmunophenotypes for Tregs
)extramer, tetramer andlor ELISPOT assay. to enume
antigen-specific cytokine secreting T-cells
HC and confocal staining for tumor antigens and T
and Ts, MDSC rn the tumor microenvironment
Protocol: A Phase II Single Amr Shrdy of Higlr-Dose IL-2 and lpilinruruab irr Patients rvith Lluesectable Stage
III and Stage IV lv{elauorua
'Only patients rvho qualify for entry into the study and consenl to the procedure will have a tumor biopsy (prior to
study). Studies will include immunohistochernistry and confocal microscopy, ex vivo analysis of base line tumor
infiltrating lymphocytes for pre-existing anti-tumor immune response and to compare w'ith post-treatment
samples.
19 Jrrll' ltll5 Yersion: -l.fl