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 Singte Arm Stud
lpilimumab in patients with Unresectabte stage ilr and
Stage lV Melanoma
Study Protocol and Statisti.utnnrtyri, pt.,r; lrf"r*d
Consent Form Main
0B / 1.1./ 20L6; 09 / 17 / 201.5
NCT number:

ilffiti,iJ$ti,'J:ll*'*" 
Shrdv of Higir-Dose IL-i a,d Ipilir,urrab in parie*ts u'irh rrruesectabre srage
Prilcrpal hrt.estigaror: f
6.2.3 Treatment Visits
6.2.3.a lnduction Treatment
Patients will have baseline blood tests and immune monitoring blood drawn prior to
receiving study medications. where indicated, a history and physical examination will also
be done' Patients will receive ipilimumab (10 mg/kg) as described by intravenous injection
over 90 minutes every three weeks for four total treatments. Any adverse events will be
recorded.
For patients receiving ipilimumab in the out-patient setting, they will be admitted to the in-
patient lL-2 unit on the same day as completing cycles 2 and 3 of ipilimurnab. The patients
should undergo routine screening for lL-2 as per institutional guidelines and begin treatment
on the same evening as ipilimumab administration. lL-2 will be administered at 600,000
lU/kg every 8 hours per institulional guidelines.
6.2.4 Maintenance Treatment
subjects will receive protocol therapy (a single 10 mglkg lv dose given every 12 weeks)
starting at week 24.
Follaw-up Visifs
6-2.5 study completion or Earry Discontinuation visit
At the time of study early withdrawal, the reason for early withdrawal and any new or
continuing adverse events should be documented. The "subject Off Study Form,,should be
completed.
6.2.6 Study Drug Discontinuation
lf study drug administration is discontinued, the reason for discontinuation will be recorded.
6.2.7 Long Term Follow up
Patients will be followed up every 6 months by phone for survival status if patients are
unable to visit the clinic.
6.3 Details of procedures
6.3.1 Study Materiats
will provide ipilimumab at no cost for this study. lL_2 is
commercially available
?9 Jrdy 2015 Yerrion: j.0

Principal hn'eslieator:
#iifi1,*.'l}T,L:llfl|| *"'Shrdv of High'Dose IL-l a'el lpili'rur,ab in parienrs w.irh Lrru.esecrable srapre
All patients who receive at least one dose of ipilimumab will be considered evaluable for
safety parameters' Additionally, any occurrence of nonserious or sAE from time of first drug
administration, up to and including follow-up visits, will be reported. see section g: Adverse
Event Reporting.
safety will be evaluated for all treated patients using the National cancer lnstitute (NCl)
common Terminorogy criteria for Adverse Events (crcAE), version 4.0
(http://ctep'cancer'gov). safety assessments will be based on medical review of adverse
event reports and the results of vital sign measurements, physical examinations, and clinical
laboratory tests.
7. Criteria for Evaluation
7.1 Safety Evaluation
Refer to the NCt CTCAE, Version 4.0 (http:llctep.cancer.gov).
7.2 Efficacy Evaluation
7'2' 1 Definition of Measurable/Non -Measurable and lndex/Non-lndex Lesions
Definitions of lesions are based on mWHO criteria
7-2.2 Dellnitlon of Measurable and Non-Measurable Lesions
7 '2'2'a Measurable Lesions are lesions that can be accurately measured in lwo
perpendicular diameters, with at least one diamet er z Zo mm and the other dimension z
10 mm with conventional techniques (10 mm x 10 mm for spiral CT). The area wiil be
defined as the product of the largest diameter with its perpendicular. Skin lesions can be
considered measurable.
7 '2'2b Non'Measurable (evaluable) Lesions are all other lesions, including
unidimensionally rneasurable disease and small lesions (lesions without at least one
diameter ) 20 mm by conventionar techniques), and any of the fofiowing:
* Lesions occuring in a previously irradiated area (unless they are documented as
new lesions since the completion of radiation therapy), bone lesions, leptomeningeal

i'ijfitiliiT,:,:j:ii:Amr shrdl'of High'Dose IL-? and rpili,rurmb in parie*ts wirh uruere$nble Suge
Principal In.-ertigoror, f
disease' ascites, pleural or pericardial effusion, lymphangitis cutis/pulmonis,
abdominal masses that are not pathologically/cytologically confirmed and followed by
imaging techniques and cystic lesions.
* All measurable and non-measurable lesions should be measured at screening and at
the defined tumor assessment timepoints (see section 5, Table 2). Extra
assessments may be performed, as clinically indicated. if there is a suspicion of
progression.
7.2.3 Definifion of lndex/Non-lndex Lesions
All measurable lesions. up to a maximum of five lesions per organ and ten lesions in
total, should be identified as lndex lesions to be measured and recorded on the medical
record at Screening. The index lesions should be representative of all involved organs. ln
addition, rndex lesions should be selected based on their size (lesions with the longest
diameters), their suitability for accurate repeat assessment by imaging techniques, and how
representative they are of the patient's tumor burden. At screening, a sum of the products of
diameters (sPD) for all lndex lesions will be calculated and considered the baseline sum of
the products of diameters. Response criteria to be followed are listed below. The baseline
sum will be used as the reference point to delermine the objective tumor response of the
rndex lesions at tumor assessment (TA).
Measurable lesions, other than lndex lesions, and all sites of non-measurable disease. will
be identified as non-index lesions" Non-index lesions will be recorded on the medical record
and should be evaluated at the same assessrnent time points as the lndex lesions. ln
subsequent assessments, non-rndex lesions will be recorded as "stable or decreased
disease." "absent," or "progression."
7.2-4 Evaluation of rumor Response Using mwHO criteria
The mWHo criteria were developed as a hybrid tumor response classification system using
elements of both the wHo and RECIST criteria in an attempt to more accurately measure
tumor lesions and estimate tumor responses. Please see tumor measurement worksheet in
Appendix
7.2-5 Definition of lndex Lesion Response Using mWHO
complete Response: comprete disappearance of ail index resions.
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iiffi'li.'iT*ll:;,Jil; *" st.dv of High-Dose IL-? ancl lpilinrurrab i. parie,ts u,irh rrruesee.tarrre staee
r
Panlal Response: Decrease, relative to baseline, of 500/o or greater in the sum of the
products of the two largest perpendicular diameters of all index lesions
stable Disease: Does not meet criteria for complete or partial response, in the absence of
progressive disease. subject with PR or cR that is not confirmed after at least 4 weeks
are scored as SD unless they have new primary lesions.
Progressive Disease: At least 25% increase in the sum of the products of all rndex lesions
(taking as reference the smallest sum recorded at or following baseline) and/or the
appearance of any new lesion(s).
7.2.6 Definition of Non -rndex Lesion Response using mwHo
cornplete Response: comprete disappearance of ail non-index lesions.
stable Disease: A decrease or tumor stabilization of one or more non-index lesions.
subject with PR or cR that is not confirmed after at least 4 weeks are scored as sD
unless they have new primary lesions.
Progressive Disease: Progression of non-index lesion(s) (e.g., an increase in pleural
effusions, or other fluid collections defined as an approximate doubling of the volume
which was present at baseline or nadir, unless there is radiographic evidence of a
benign cause for the fluid collection or the effusion is cytologically negative for malignant
cells).
7.2.7 Determination of Overall Response Using mWHO
overall Response (oR) is determined as the combination of assessments of index and non-
index lesions using the following criteria:
Table 7 mWHO Response Criteria
Non-lndex
Lesion 
New Lesions
Assessment
lndex Lesion
Assessment
Overall
Response
CR
CR
PR
SD
PD
CR
SD
CR or SD
CR or SD
Any
No
No
No
No
Yes or No
CR
PR
PR
SD
PD
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ili::-l;i.'*ilHi:if tu:, Shrtlv of Hish-Dose IL-l ancl lpilinrur,ab in patie,rs *:irh Lrruesectnrrle srase
Prilcipal Iuresrigarol f
Any
Any
PD
Any
Yes or No
Yes
PD
PO
Best oR is the best conflrmed response designation over the study as a whole, recorded
between the date of first dose until the last tumor assessment for the individual patient in the
study' The assessment of respons e al llweeks has particular emphasis due to the
mechanism of action of ipilimumab inducing immune responses as basis for clinical
responses' For the assessment of best oR, all available assessments per patient are
considered' cR, PR and PD determinations included in the best oR assessment must be
confirmed by a second (confirmatory) evaluation meeting the criteria for response and
lhe criteria for re
are first met
lmaging of the chest, abdomen and pelvis is required at screening (ie, baseline) and at each
tumor assessment visit, regardless of the location of known metastases. $imilar methods of
tumor assessment and similar techniques must be used to characterize each identified and
reported lesion at screening and during subsequent tumor assessments. lmaging-based
evaluation is preferred to clinical examination.
lf progressive disease is assessed based only on a new lesion(s) found on bone scans,
additional imaging studies of the lesion(s) should be performed to confirm the matignant
nature of the new findings on the bone scan. lncreased intensity of uptake in previously
abnormal areas on bone scans is not considered progressive disease. unless the lesions
seen on the correlative imaging studies performed of this area meet the criteria for
progression' New areas of abnormal uptake on a bone scan represent progressive disease.
8. INVEST|GATIONAL PRODUCT: tptLtMUMAB
The investigational product is defined as a pharmaceuticalform of an active ingredient being
tested as a reference in the study, whether blinded or unblinded. ln this study, the
investigational product is ipilimumab.
other medications used in the study as support or escape medication for preventative,
diagnostic, or therapeutic reasons, as components of the standard of care for a given
diagnosis, are considered noninvestigational products. ln this protocol, non-investigational
product{ s ) i s/are : I nterleukin- 2 (lL-2, aldesleuki n ).
8.1 ldentification
lpilimumab is available in 5 mg/mL single-use vials (40 mL). The sterile solution in the vial is
clear and colorless. lpilimumab is administered via intravenous infusion only.
39 July 2015 \renicn: 1.0

irIfi1;*" L i,:f:::i:An, 
shrdv of Hisli-Dose IL-l a*<l lpiliruu*rab i. parie'ts u,irh Lrru.ese*abre Srase
r
o.t racKagtng and Labeling
8MS will provide ipilimumab at no cost for this study. lpilimumab wiil be provided in open-
label containers' The labels will contain the protocol prefix. batch number, content, storage
conditions' and dispensing instructions along with the lnvestigational New Drug (tND)
caution statement' lpilimumab will be supplied at a concentration of 5 mglml in vials
containing 40 mL solution.
8.3 Storage, Handling, and Dispensing
8.3.1 $torage
lpilimumab must be stored in a secure area according to local regulations. The investigator
must ensure that it is stored in accordance with the environmental conditions as determined
by BMS and defined in the lnvestigator Brochure or smpc/reference label. lpilimumab must
be stored at a temperature,:: 2oC and ::i goC.
8.3.2 Handling and Disposat
As with all injectable drugs, care should be taken when handting and preparing ipilimumab.
whenever possible, ipilimumab should be prepared in a laminar flow hood or safety cabinet
using standard precautions for the safe handling of intravenous agents applying aseptic
technique' Latex gloves are required. lf ipilimumab concentrate or solution comes in contact
with skin or mucosa, immediately and thoroughly wash with soap and water. Afier flnal drug
reconciliation' unused ipilimumab solution should be disposed at the site following
procedures for the disposal of anticancer drugs.
8.3.3 Dispensing
It is the responsibility of the investigator to ensure that ipilimumab is only dispensed to study
subjects' The ipilimumab must be dispensed only from official study sites by authorized
personnel according to local regulations.
8.4 Drug Ordering and Accountability
8.4.1 lnitiat Orders
Following submission and approval of the required regulatory documents,
ipilimumab may be ordered from 
]
must complete a Drug Request
Please fax to
Form and email it to
The study Pt
a supply of
(or delegate)
and
electronically
39 July 2015 Yeruiorr: j.(l
you cannot send the form

frT:ti;*iit.i*;Tif ** shrttv of High'Dose IL-r and Ipiliruruilab in parie,rs rvirh Lrruesectar:le srage
r
tptttmumab vials (40 mL) are shipped in quantities of ten. Alrow 5 business days for shipment
of drug from BMS receipt of the ipilimumab clinical suppry shipment Request form. Drug is
protocol specific, but not patient specific.
All products will be shipped via Federal Express in a temperature-controlled contarner.
shipments will be made from BMS on Monday through rhursday for delivery onsite Tuesday
through Friday' There will be no weekend or holiday delivery of drugs. lt is possible that
sites may have more than one ipilimumab clinical study ongoing at the same time. lt is
.fo
help segregate product for this study from other investigationat or marketed product, stickers
bearing the BMS protocol number will be provided and should be affixed to the front of the
outer carton just above the company names so as not to obscure any marking.
8.4.2 P articipating Sites
Participating sites should refer to the pharmacy
ordering, storage, accountability and destruction.
A completed il 
lnvestigational Drug Request Form
suomtned for processing by 2pm EST. When additional
agent are requested for a previously established patient,
Product Accountability Form must accompany the request
Manual for additional information on drug
For assistance with orders contact:
for a specific patient must be
supplies of the investigational
a copy of the lnvestigational
for auditing purposes.
Protocol Versiou Date: 39 Jul1.?015 1,'".r1.ru, ,.0
F

ilili'i,;tJi[T,,'fii::f A.rr Snrrll' of Hieh'Dose IL-] and Ipilir,u,rau in parie,rs u,irh Lrruesectabre srase
Principal Ir.-"trigoror, f
. Patient must be registered in Oncoree at
' Ancillary sites should allow up to five (5) working days for delivery of lp to allow for
internal processing and shipping via UpS next Oayiii.-, -
' The initial drug supply will be for the 4 doses of the induction phase. Future drug
request will be limited to a twelve (12) week rupprv ii-mainrenance doses) or less for
each patient per order. To receive further orugi 'supplies, a new lnvestigational Drug
Request Form must be compreted. -when 
3$i,,g!.r1:;;;". of the rp are requested for
ffifffiXlj;:X:"tned 
patient, a copv or the DARF must accompanv ine iequesr ror
' The shipping destinatron specified on the order form must be the same as the intended
storage location for the transferred agent,
. A copy of the lnvesti
the lP shi
The receiving site 
"
iY^b:-::gil"g in the prorocot drus accountabitity
or th e i n u.. i i g 
"t 
i "',, 
i' In:X':"'''ffi ":i$ T':31X, Ji i."j.; 
^ 
$J 
-J,:i *::* ":X, f:
request for auditing purposes.
of the DARF must accompany the
' 
lP is not to be transferred or stored at any other location except the location specified on
the request form and DARF.
8.5 lpilimumabAccountability
It is the responsibility of the investigator to ensure that a current record of ipilimumab
disposition is maintained at each study site where ipirimumab is inventoried and disposed.
Records or logs must comply with applicable regulatrons and guidelines, and should include:
. Amount received and placed in storage area.
. Amount currenfly in storage area.
. Label lD number or batch number and use date or expiry date.
' 
Dates and initials of person responsible for each ipilimumab inventory entry/movement.
' 
Amount dispensed to and returned by each subject, including unique subject identifiers.
' 
Amount transferred to another arearsite for dispensing or storage.
. Non-study disposition (e.g., lost, wasted, broken).
. Amount destroyed at study site.
8.6 lpilimumab Destruction
lf ipilimumab is to be destroyed on site, it is the investigator's responsibility to ensure that
arrangements have been made for disposal and that procedures for proper disposal have
Receipt
3lgl9!91 Versiol Dare: 39 Juli, l0l5 \renion: j.0
F

fiffi"i,*JifTr:ililif 'turu Shrdv orHisir'Dose IL-i a,rl lpiliuru,rab in parie*rs *'irh uruerecrabre srage
Principal hn.errigoror, f
been established acaording t,o applicable regulations, guidelines, and institutional
procedures. Appropriate records of the disposar must be maintained.
9. ADVERSE EVENT REPORTING
9.1 Collection of Safety lnformation
An Adverse Event (AE) ts defined as any new untoward medical occurrence or worsening
of a pre-existing medical condition in a patient or clinical investigation subject administered
an investigational (medicinal) product and that does not necessarily have a causal
relationship with this treatment- An AE can therefore be any unfavorable and unintended
sign (including an abnormal laboratory finding, for example), symptom, or disease
temporally associated with the use of investigational product. whether or not considered
related to the investigational product,
Adverse events can be spontaneously reported or elicited during open-ended questioning,
examination' or evaluation of a subject. (ln order to prevent reporting bias, subjects should
not be questioned regarding the specific occurrence of one or more AEs.)
9.1.1 Serious Adverse Events
A serfous adverse event (sAE) is any unloward medical occurrence that at any dose:
' 
results in death
' 
is life-threatening (defined as an event in which the subject was at risk of death at the
time of the event, it does not refer to an event which hypothetically rnight have
caused death if it were more severe)
' 
requires inpatient hospitalization or causes prolongation of existing hospitalization
(see note below for exceptions)
. results in persistent or significant disability/incapacity
. is a congenital anomaly/birth defect
' is an important medical event, defined as a medical event that may not be
immediately life{hreatening or result in death or hospitalization but, based on
appropriate medical and scientific .iudgment, may jeopardize the subject or may
require intervention (eg, medical, surgical) to prevent one of the other serious
outcomes listed above. Examples of such events include but are not limited to
intensive treatment in an emergency department or at home for allergic
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization.
?9 Jull' l0l5 \:errion: J.f)

,?ri::t;i.tl[T,L:i:if a:rr Studv orHigh'Dose IL-r and Ipilinru,rab i,r parie,*s u.ith rrruese*abre Srage
I
Aoolllonally' suspected transmission of an infectious agent (eg, any organism, virus or
infectious particle' pathogenic or non-pathogenic) via the study drug is an sAE. Although
overdose' and cancer are not always serious by regulatory definition, these events must be
handled as sAEs' Any component of a study endpoint that is considered related to study
therapy (eg' death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must
be reported) should be reported as an SAE
NorE: The following hospitalizations are not considered sAEs in BMS clinicalstudies:
' a visit to the emergency room or other hospital department for less than 24 hours that
does not result in admission (unless considered an "important medical event,,or a life-
threatening event)
. elective surgery, planned before signing consent
' 
admissions as per protocor for a pranned medicar/surgicar procedure
' 
routine health assessment requiring admission for baseline/trending of health status (eg,
routine colonoscopy)
' 
rnedicallsurgical admission for purpose other than remedying ill health state and was
planned prior to entry into the study. Appropriate documentation is required in these
cases
' 
admission encountered for another life circumstance that carries no bearing on health
status and requires no medical/surgical intervention (eg, lack of housing, economic
inadequacy, care-giver respite, famiry circumstances, administrative)"
Note that pregnancy in and of itself is not considered an sAE unless one of the above serious
criteria has been met' However. all pregnancies, regardless of outcome, must be reported to
/yvl 
rgv tv
r:,::::'::-::'"n:"ncyReportFormandfollowedtoouteome'@
on reporting pregnancies.
iect. See Section g.3.4 for instructions
Note: Pregnancy Forms will be located in your study binders along with instructions.
9.1.2 Nonserious Adverse Events
A nonserious adrrerse event is an AE not crassified as serious.
9.2 Assignment of Adverse Event lntensity and Relationship to
lnvestigational product
29 Jull'2015 \'s15i*r, 3.,

ilffi,,lrtJi\.1Trffi:if '{mr shrr{v of Hish-Dose IL-f aricl lpili,uu'ab in parie'rs rvirh Lrruereciabte srase
Principal Inr.e.srigator: f
The following categorimdefinitions of causar rerationship to investigationar product as
determined by the investigator should be used:
' Related: There is a reasonable causal relationship to investigational product
administration and the adverse event.
' 
Not Related: There is not a reasonable causal relationshrp to investigationat product
administration and the adverse event.
The expression "reasonable causal relationship" is meant to convey in general that there are
facts (e'g', evidence such as dechallenge/rechallenge) or other arguments to suggest a
positive causal relationship.
9.3 Collection and Reporting: AEsISAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning,
examination' or evaluation of a subject. (ln order to prevent reporting bias, subjects should
not be questioned regarding the specific occurrence of one or more AEs.)
lf known, the diagnosis of the underlying illness or drsorder should be recorded, rather than
its individual symptoms. The following information should be captured for all AEs: onset,
duration' intensity, seriousness. relationship to investrgational product, action taken, and
treatment required. lf treatment for the AE was administered. it should be recorded in the
medical record.
The investigator shall supply the sponsor and Ethics committee with any additional
requested information, notably for reported deaths of subjects.
9.3.1 Serious Adverse Events
Following the subject's first administered dose of study treatment in the study, all sAEs, as
defined in Section 9.1.1, must be collected, including those thought to be associated with
protocol-specified procedures. All sAEs must be collected that occur within g0 days of
discontinuation of dosing of the investigational product. lf applicable, sAEs must be
collected which relate to any later protocol-specified procedure (eg, a follow-up skin biopsy)
or after 90 days if a causal relationship is suspected f 
will notify BMS of any SAE
occurring after this time period that is believed to be relatil the investigational product or
protocol-specifi ed procedu re.
All SAEs whether related or unrelated to the ipilimumab, must be immediately reported to
TI 
(by the investigator or designee) within 24 hours of becoming aware of the event.
lf only limited information is initially available,
SAE form must be kept on file at the study site.
follow-up reports are required. The origrnal
Protocol Versir:u Dale: 29 Jul1,20l,s \:eri;ron: j.0

Protocol: A Phase II Single Anu Shrdl' of High-Dose IL-l. and lpilinruurab in Parients u,ith LLuerectnble Stase
iII and Stage I\' \lelanourn
Principal Int'"srigotor, f
Please refer to the SAE Report Form Completion Manual for instructions on completing the
form.
Study sites should report all $AEs to
by email or fax to:
A copy of all SAEs wiil be forwarded by
including the
Serious adverse events, whether related or unrelated to investigational product, must be
recorded on the SAE Report Form and submitted within 24 hours to Theradex€r of site
awareness of the event in order to comply with regulatory requirements. An SAE report
should be completed for any event where doubt exists regarding its status of p.-g-11o_11g1;re-qg
All SAEs must be immediately reported by email (preferred) or fax lf only limited
information is initially available, follow-up reports are required. (Note: Follow-up SAE reports
should include the same investigator term(s) initially reported.) ln selected circumstances,
the protocol may specify conditions that require additional telephone reporting. lf notrfication
occurs to J 
by telephone. a completed SAE Report Form is expected within 24
hours.
lf the investigator believes that an SAE is not related to the investigational product, but is
potentially related to the conditions of the study (such as withdrawal of previous therapy, or
a complication of a study procedure). the relationship should be specified in the narrative
section of the SAE page.
Protocol Versiol Date: 19 Jull'lQl5 yerrion: j.0

frT:"j;:il[T,:,::* 
A,r, shrd-v of Hish-Dose IL-l a,cl lpili.*urnb i, parie,rs u,irh Lku^esectarrre srage
Principal hrt-esrigaror, f
lf an ongoing sAE cM@n 
its intensity or relationship to the investigational product, a
fofiow-up sAE report shourd be sent immediatery 
" I 
A, d;_;p intormation
becomes available it should be sent immediately ulifr u'," same procedure used for
transmitting the initial sAE report. All sAEs should be foltowed to resotution or stabitization.
9.3.2 Handting of Expedited Safety Reports
ln accordance with local regulations, Theradex6l will notify investigators of all sAEs that are
suspected (related to the tnvestigational product) and unexpected (r.e., not previously
described in the lnvestigator Brochure). ln the European union (EU), an event meeting
these criteria is termed a suspected, unexpected serious Adverse Reaction (susAR).
lnvestigator notification of these events will be in the form of an expedited safety repod
(ESR)
other important findings which may be reported by the sponsor as an ESR include:
increased frequency of a clinically significant expected sAE. an sAE considered associated
with study procedures that could modify the conduct of the study, lack of efficacy that poses
significant hazard to study subjects, clinically significant safety finding from a nonctinical
(e'g', animal) study, important safety recommendations from a study data monrtoring
committee, or sponsor decision to end or temporarily halt a clinical study for safety reasons.
Upon receiving an ESR from BMS (or designee), the investigator must review and retain the
ESR with the lnvestigator Brochure. where required by local regulations or when there is a
central IRB/lEc for the study, the sponsor will submit the ESR to the appropriate IRB/lEC.
The investigator and lRBllEC will determine if the informed consent requires revision. The
investigator should also comply with the lRBllEC procedures for reporting any other safety
information.
ln addition, suspected serious adverse reactions (whether expected or unexpected) shall be
reported uv f 
to the relevant competent health authorities in all concerned countries
according to local regulations (either as expedited andlor in aggregate reports).
9.3.3 Nonserious Adverse Events
The collection of nonserious AE information should begin at initiation of investigational
product' Nonserious AE information should also be collected from the start of a placebo
lead-in period or other observational period intended to establish a baseline status for the
subjects.
lf an ongoing nonserious AE worsens in its intensity, or if its relationship to the
investigational product changes, a new nonserious AE entry for the event should be
completed' Nonserious AEs should be followed to resolution or stabilization, or reported as
SAEs if they become serious. Follow-up rs also required for nonserious AEs that cause
29 July ?015 Yerrion: -i.0

hotocol: A Phase II sirrgle 'furl Shrdy of High-Dose IL-? and Ipilimunrab in paiienrs rvirh Lrruese*able Srage
III and Stage IV Nlelauorua
Princrpal Iuo'errigotor, f
interruption or discontinuation of investigational product, or those that are present at the end
of study participation' subiects with nonserious AEs at study cornpletion should receive
post-treatment follow-up as appropriate.
All identifled nonserious AEs must be recorded and described in the medical record.
9.3.4 Pregnancy
sexually active wocBP must use an effective method of birth control during the course of
the study, in a manner such that risk of failure is minrmized. Before enrolling wocBp in this
clinical study' the investigator must review the guideline about study participation for
wocBP which can be found in the GCP Manual for lnvestigators. The topics include the
following:
' 
General lnformation
. 
lnformed Consent Form
. Pregnancy prevention lnformation Sheet
. Drug lnteractrons with Hormonal Contraceptives
. Contraceptives in Current Use
. Guidelines for the Follow-up of a Reported pregnancy.
Before study enrollment, WOCBP must be advised of the importance of avoiding pregnancy
during study participation and the potential risk factors for an unintentional pregnancy. The
subject must sign an informed consent form documenting this discussion.
All wocBP MUST have a negative pregnancy test within 24hours before receiving
ipilimumab. The minimum sensitivity of the pregnancy test must be 25 lU/L or equivalent
units of HCG. lf the pregnancy test is positive, the subject must not receive ipilimumab and
must not be enrolled in the study.
aIIWOCBP shoutd
instructed to contact th
t
t (e.q.. missed
time durinq studv participation.
lf' following initiation of the investigational product, it is subsequengy discovered that a study
subject is pregnant or may have been pregnant at the time of investigational product
exposure' including during at least 6 half-lives(9O days afier treatment) after product
administration, the investigational product will be permanenily discontinued in an
appropriate manner (eg, dose tapering if necessary for subject safety). The investigator
must immediately notify TheradexCI of this event and record the pregnancy on the Theradex@
Pregnancy Report Form (not an SAE form) in accordance with the SAE reporting
Protocol Version Date: 19 July.2t)15 \:erion: J.0
F

procedures (refer to seitlon g.g.1). lnitial information on a pregnancy must be reported
immediately to,lllf, 
and the outcome information provided once the outcome is
illfrtriil*Tr:,:||fll,| 
Ann shrdv of High'Dose IL-3 a*cl Ipilinrurnb i* parie,rs wirh Lrruerectable srage
Principal hrr"errignror:
male study participant should be
this pregnancy will be collected on
known. ft,e r --- 
pregnancy Report Form wiil be forward"d - 
ro, on*aro
notification til
Any pregnancy that occurs in a female partner of a
reported to the Theradexe Safety Desk. lnformation on
tneJ 
pregnancy Report Form.
Protocol-required procedures for study discontinuation and follow-up must be performed on
the subject unless contraindicated by pregnancy (e.g., x-ray studies). other appropriate
pregnancy follow-up procedures should be considered if indicated. ln addition, the
investigatormustreporttofasinstructedabove,follow.upinformationregarding
the course of the pregnancy, including perinatal and neonatal outcome using the Theradexo
Pregnancy outcome Report Form. lnfants should be followed for a minimum of g weeks.
9.3.5 Other Safety Considerations
Any significant worsening noted during interim or final physical examinations,
electrocardiograms, x-rays, and any other potential safety assessments, whether or not
these procedures are required by the protocol. should also be recorded in the medical
record.
10. STATISTICALMETHODOLOGY
Descriptive statistical will be used, except where othenarise specified. continuous variables
will be presented by summary statistics (such as mean, median, standard error and ggyo Cl)
and the categorical variables by frequency distributions (i.e., frequency counts, percentages
and 90o/o Cl).
10.1 Sample size considerations
The primary goal of this clinical trial is to determine the clinical objective response rate within
the first 24 weeks of ipilimumab and lL-2 in patients with unresectable Stage lll and IV
melanoma Secondary endpoints include safety, feasibility, overall survival, one year and
two year survival, progression-free survival, best overall response, and frequency of effector
CD8+ T cells and CD4+Foxp3+ regulatory T cells.
19 July 2QI5 \,'errion: i.0

ilffit,iJii1i:,:lli: '{'ntr shrilv of Hish-Dose IL-l anrllpili,ru,ub i, parie'ts.*,irh Lrruese*arrre stage
r
ror sample size calculations, we assume that obiective response rate for ipilimumab alone
is no greater than 14o/a aod for lL-2 is no greater than 17y0. Based on these assumptions.
sample size calculations based on proiected rates of response compared to ipilimumab and
lL-2 alone are shown in Table 8. ln order to detect a clinicar objective response rate of zga/o
a sample size of 45 subjects are needed to show that the combination is better than
ipilimumab alone and 82 subjects are needed to show improvement compared to tL-2 alone.
Thus' we will seek to enroll 82 subjects. This results in 80olo power to detect a meaningful
response at alpha=0'05 and one-sided testing under one sample binomial distribution. lf a
28olo obiective response rate is reached then the combination will be considered significant
and further studies would be warranted.
It is anticipated that accrual will be at a rate of 5-10 patients per month and. thus, accrual
should be completed within 12 months. we anticipate registrati on of gr-g2 total patients to
allow for patients who do not comprete treatment with fuily evaruabre data.
Table 8. sampre size carcurations for this crinicar triat
10.2 Patient populations
The intent-to{reat (lTT) population is defined as all patients who have been registered to
receive study treatment in this protocol. The PP population is defined as all patients who are
eligible for the study and received at least two cycles of treatment.
10.3 statisticar Methods for primary objectives
The best objective response rate as determined by mwHo criteria at or before week 24 of
treatment will be defined as the ratio of the number of patients whose best response is a cR
rlected Rare of IpI+II_j
attrple \lze lreeded k) attalrl
09'o power to cttmpare rvrflr
.106 r'are ibr IPI alone
arnple srze rrc'r'rled to attain
0o.ii porvcr to conlpare u,ifh
179.0 rate tbr ILI alone
Protocol \:ersiou Dare: 29 Jul1. l0l5 \.erricrn; j.0

ilii:i;*Ji|Ir:fifff 
'turu st.riv of Hieh-Dose IL-] ancl lpilin*,,ab i, parie,rs *.irh Lrruesecrarrre.$rage
Principal Irn *rrigutor, f
or PR divided ov tGloiatffiuer of patients enrolted who have baseline and post-treatrnent
assessments' Confirmation of responses requires a scan at least 4 weeks after the initiat
response and this may occur after the initial 24 week period. The analysis of this primary
endpoint will be performed using exact one-sample binomial tests where the objective
response rate of lpilimumab and lL2 combination will be compared with published response
rate of lpilimumab alone and lL-2 alone. . The primary analysis will be done on the lrr
population but a confirmatory analysis in the PP population will also be conducted. patients
will have formal documentation of their disease status at the week 12 and 24imaging time
point and the status of each patients response will be determined if they are withdrawn for
any reason at the time of going off study.
1a.4 Statisticar Methods for secondary objectives
14.4.1 Secondary Efficacy Endpoints
overall survival (o8): This is defined as the time from the date of registration to the date of
death from any cause. os time will be censored at the last date the patient is known to be
alive to the date of death; when the confirmation of death is absent or not known the date
last known alive will be used. Patients are censored at the date of enrollment if no additional
follow-up data are obtained. The median overall survival, survival al 1 yearand survival at 2
and 3 years will be estimated using Kaplan-Meier method and their 90o/o confidence
intervals will also be reported.
Progression'free survival (PF$): This is defined as the time from the date of registration
until the date of documented disease progression or death. This must be based on at least
two imaging studies at least 4 weeks apart confirming disease progression. pFS will be
based on the flrst documented imaging study to show disease response/progression based
on mWHo guidelines- The PFS will be estimated using Kaplan-Meier method and the
median PFS and its g0o/o confidence interval will be reported.
Best overall Response Rate: The best overall response rate is determined by the study
investigator once all the data for an individual patient is known during the treatment period.
The best overall response is defined as the best response across all time points (for
example, a patient who has $D at first assessment, PR at second assessment, and pD on
39 July f0l5 Yer$ion: J.Il

l:oto...r], A Phase II Single .tu.nr Snrdl. of High-Dose IL-3
I1I ancl Stage I\' \lelauournr
rast assessment has a best overall response of
point at least 4 weeks later. The best overall r
the rate reported.
Disease control rate (DCR): The rate of patient
disease response will be determined by modified
Safety and toxicity
ncl Ipilinturmb in patients u,ith Liruesectable Srage
are confirmed at a subsequent time
will be tabulated for all patients and
who achieve a complete. partial or stable
H0 criteria and recorded.
) The best overall response rate will be
determined since some patients may exhibit d
responses that occur after the week 24
would be captured by the best overall
assessment; therapeutic benefit for these pati
response and in survival data. A CR rnust be
with a CT scan or appropriate
imaging at 4 weeks. When SD is believed to
the best response. it must also meet the
protocol specified time of initiating within 12
s of sta(ing treatment and sustained for
at least 12 weeks. For example, if a patient has
D at the 6 month assessment and pD at
I be considered pD. Complete or partial
the 12 month assessment, the best response
responses may be claimed only if these
A secondary objective of this study is to oetermife the safety and toxicity of ipilimumab in
combination with lL-2. safety assessments will inllude all treated patients receiving at least
one dose ol lL-2 or ipilimumab. Patients who ar]e registered and withdraw from the trial
before receiving any study treatment will be excltfoeo from the safety analysis, but will be
followed for response and survival" safety "sres{m"nts will be based on adverse events,
laboratory data, concomitant medications, results of physical examinations and vital signs.
An tnterim safety analysis will be conducted after the first 6 patients have completed four
doses of ipilimumab. An independent DSMB wrll review the adverse events reported for
these patients and make a determrnation to procped with additional enrollment or to de_
escalate the dose of ipilimumab at 3 mg/kg.
The type of toxicity occurring and their frequency pnd severity will be noted in intention{o-
treat population' Adverse events will be ilsted by subiects within groups showing time of
onset, period of event, grade classified using the CTCAE v.4.0, relationship to disease and
outcome" lf a patient experiences multiple events that can be linked to a single adverse
event, the greatest severity and strongest investigqtor assessment of rela1on to study drug
wtll be assigned that that adverse event. Since lL-2 and ipilimumab are both FDA approved
;ffiI,uDare: 
3eJ*r1.r0r5\-e*ion:.i.0 
I

il"ffi'i,iJili-ir:Hfff Afl, Strrdv of High'Dose IL'J a,lcl rpilin[urrab in parienrs u.irh Lrru.eser..tntrle srage
Principal Ir,r."rrigorol f
agents with defined toxicrty profiles, the number of events in each classification of severity
and relationship to treatment will be tabulated for each patient and summarized by treatment
arm' This will allow detection of new or more sustained adverse events with the combination
regimen.
10.4.2 lmmune Responses
Evaluation of immunological responses will be primarily based on the breadth and
magnitude of cellular responses (see section 10 for more detairs). The frequency of tumor
specific T cells and regulatory cells including CD4+ Tregs and effector CDg+ will be
measured pre-treatment and various days post-treatrnent in the tumor and peripheral blood.
Treatment effect for each patient will be measured as paired differences between pre and
post measurements of these parameters at various times. Transformation of the data will be
performed if appropriate, e.g. log transformation, and hence treatment effect will be
expressed on a log scale. For further information on the statistical analysis of the immune
responses see Section 10.7.
11. ADMINISTRATIVE SECTION
11.1 compliance with the protocor and protocor Revisions
The study must be conducted as described in the finar approved protocor
approval signed by the chairperson or designee of the rRB(s) must be
protocoloffice before activating the study.
All revisions (protocol amendments, administrative letters, and changes to the informed
consent) must be submitted to the central protocol office for submission to BMS. The
investigator should not implement any deviation or change to the protocol without prior
review and documented approval/favorable opinion from the IRB of an Amendment. except
where necessary to eriminate an immediate hazard(s) to study patients.
see also 21cFR for definitions of amendment and requirements.
' 
lnvestigators must.follow all applicable requirements for protocol development. including
21 CFR 312.23{a)(6) and tCH duidetines part 6.
' 
see also 21 cFR 1 1, 50, s6, 312, and 314 for appticabte lnvestigator/sponsor
information regarding study execution and conduct related to protocol requirements.
. Docurnentation of
sent to the central
Prototol Versiou Date: t9 Jull, l0l-{ \:errion: -i.tt

i'ijli"i;*.tilltiili:i: 'tur' shrdv or Hish-Dose IL-l a,rcl lpiri.ru,mb in paiie.rs *.ilh Lrru'erecabre Sta;re
Principal Iuresrigator, f
11.2 lnformed ConiEnt
lnvestigators must ensure that subjects, or, in those situations where consent cannot be
given by subjects, their legally acceptable representative, are clearly and fuly informed
about the purpose, potential risks, and other critical issues regarding clinical studies in which
they volunteer to participate. Freely given written informed consent must be obtained from
every subject or, in those situations where consent cannot be given by subjects, their legally
acceptable representative, prior to clinical study participation, including informed consent for
any screening procedures conducted to establish subject eligibility for the study.
The rights, safety, and well-being of the study subjects are the most important
considerations and should prevail over interests of science and society.
11.3 Records and Reports
An investigator is required to prepare and maintain adequate and accurate case histories
designed to record all observations and other data pertinent to the investigation (e.g.
medical record)) on each individual treated with lpilimumab or entered as a control in the
investigation. The investigator is required to retain, in a confidential manner, the data
pertinent to the study.
11.4 Good Clinical practice
This study will be conducted in accordance with Good Clinrcal practice (GCp), as defined by
the lnternational conference on Harmonisation (lcH) and in accordance with the ethical
principles underlying European union Directive zaalaaEc and the united states code of
Federal Regutations, Tifle 21, part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any
amendments and the subject informed consent will receive lnstitutional Review
Board/lndependent Ethics committee (lRB/lEc) approvallfavorabte opinion prior to initiation
of the study.
All potential serious breaches must be repofied to BMS immediately. A serious breach is a
breach of the conditions and principles of GCP in connection with the study or the protocol,
which is likely to affect, to a significant degree, the safety or physical or mental integrity of
the subjects of the study or the scientific varue of the study.
Study personnel involved in conducting this study will be qualified by education, training,
and experience to pefform their respective task(s). This study will not use the services of
study personnel where sanctions have been invoked or where there has been scientific
misconduct or fraud (e.g., ross of medrcar ricensure, debarment).
!*g!qf Velsir:rr Dare: l9 Julr' l0l5 Version: .i.fl

Protocol: A Phase Ii Single Aml shld)'of High'Dose IL-3 and Ipilinlurmtr in parienrs rvirh Llu.esecrable srage
IlI and Stage I\: \{elauoura
Principal Iut'errignror, f
systems with procedures that ensure the quality of every aspect of the study will be
implemented.
11.5 lnstitutional Review Board/lndependent Ethics committee
(tRB/tEC)
Before study initiation, investigators must have written and dated approval/favorable opinion
from the IRB/IEC for the protocol, consent form, subiect recruitment materials/process (e.g.,
advertisements), and any other written information to be provided to subjects. The
investigator should also provide the IRB/IEC with a copy of the lnvestigator Brochure or
product labeling, information to be provided to subjects and any updates.
The investigator should provide the lRBllEC with reports, updates and other information
(e'g'' expedited safety reports, amendments, and administrative letters) according to
regulatory requirements or institution procedures
11.6 Records Retention
The investigator must retain lpilimumab disposition records, source documents, and case
histories designed to record all observations and other data pertinent to the investigation
(e'g' medical record) for the maximum period required by appticable regulations and
guidelines. or lnstitution procedures.
lf the investigator withdraws from the study (e.g., relocation, retirement),
transferred to a mutually agreed upon designee (e g., another
Documentation of such transfer must be provided toI
12. Laboratory Studies
12.'l collection of sampres for rmmunorogy Assessment
Approximately g0 cc of peripheral blood will be collected at each time
Table 2 for immune monitoring. All specimens should have a ,,specimen
completed by the collectrng research personnel and faxed to the central
shipping. Please refer to the Laboratory Manual for a more information.
the records shall be
investigator, IRB).
point indicated in
Submission Form"
laboratory prior to
are continuously evolving
immunologic assays, as
since immune assays and funding sources for immune monitoring
we will plan to store pBMC and serum for potential future
appropriate.
Collection of Serum: For serum collection, whole blood will be collected in two red-top (no
39 July l(.)15 Verricur: .i.tl

Ptotocol: A Plrase II Siugle .furn Shrdy of High-Dose IL-? ancl Ipilinruunb in pariertrs rvirh Llruesectable Stase
III and Srage I\.'\{elanorua
Princ ipal Iu,,'ertigo tor, f
additive) tubes- lmmediateiy prior to drawing blood, the person in charge of the procedure
will verify the subject's identity. lmmediately after the blood has been collected, a tabel
containing the appropriate subject identiflcation number and the subject,s initials is to be
affixed to the vial. serum will be stored for future studies to be determined by standards in
the field and funding in the future.
Collection of PBMC: Whole blood {80 cc) will be collected in 4 green/red top cpT
Tubestubes at the time points and in the quantities presented in Table 2. prior to each blood
draw, the patient's identity must be verified. Each vacutainer will be labeled with the
patient's study identification number, initials, sample number, and the date the samples
were taken.
HLA Typing: HLA typing will be determined by standard PCR analysis as previously
described (83)' Alternatively, HLA type can be determined by pCR-sequence specific
oligonucleotides (PCR-ssoP) to resolve major allele groups to 4 digits, with some
degeneracy e.g. HLA-A-23:01/03/05/06) ln this case, genomic DNA from PBMC is amptifted
using PCR, then incubated with a panel of different oligonucleotide probes, which have
distinctive reactivities with different HLA{ypes. The
will be
used. where oligonucleotide probes are individually attached to up to 100 distincly
fluorescent mlcrospheres. This allows the measurement of 100 different reactions in a single
tube.
Tumor Biopsy {Optional} ln selected patients tumor tissue may be obtained and submitted
for analysis of the tumor microenvironment. Biopsy samples should be obtained under
standard sterile surgical technique and placed into a sterile container. The container should
be labeled with the patient's study identification number, initials, and the date the sample
was taken.
Table 2: lmmunology and Biomarker Sampling Schedule
Time relative
to dosing
PBMC Flow
cytometry
Tumor Tissue
39 July 2015 \."errion: i.0
Study Day
Time
Serum

I Iur,^estigaror
(Hours:mins)
(CD8+ Tcells,
Tregs)
Sceening(-14
days to day 1)
Pre-dose
00:00
X
X (Once
eligibility is
determined)
Treatment Visit
r1
Pre-dose
00:00
X
x
Treatment Visit
fi2
Pre-dose
00:00
X
X
Treatrnent Visit
$3
Pre-dose
00:00
lnduction
Assessment
Follow-up #1
Pre-dose
00:00
x
X
Follow-up #2:
(Maintenance
Treatment visit
rs)
Pre-dose
0O:00
x
Y
Follow-up
S5(Maintenance
Treatment visit
f8i
Pre-dose
00:00
X
X
x
Follow-up{End
of Treatment)
$6
Pre-dose
00:00
X
X
X
Pt'otocol: A Phase II Sirrgle Ar:u Shrdy of High-Dose IL-2 ancl Ipiliruurrrab in Parients rvith Lluesectable Stage
III and Stage I\'lvlelanorua
Following the collection of whole blood or tumor tissue, the tubes/containers should be
placed in the customized packaging systems and shipped directly to the core BRS
Laboratory and ship to the following address:
Protncol \"er,qiou Date; 19 Julr'1015 Version: -1.0
r
Pase 8-l

P'otocol: A Phase II Siilgle Aflll Shrdl' of High-Dose IL-3 ancl Ipiliurtuuab in pariel.lls u.ith Llru.e ecrable srage
III and Stage I\, l{elauonra
Principal hr'ettignror, f
rr.HHrrrv )sIrIvrG>, I'r rs Ldueratory l\otlflcatlon Form should be faxed directly to the
labatt-BloodSampleScannotbeshippedonFridaysoranydaypriortoa
Prior to shipping samples, the Laboratory Notification Form should be faxed
national holiday.
12.2 Tissue processing
specimens delivered to the lab will be handled and processed according to standard sops.
Upon receipt of the Laboratory Notification Form an entry will be made and sample number
issued for the expected sample in the Tumor lmmunology Laboratory biospecimen
repository database. samples will be processed as follows:
serum samples: Red top tubes will be centrifuged, with the samples being handled one
subject at a time to avoid a mix-up. The serum will be divided into aliquots, by being
transferred to the appropriate number of cryotubes previously labeled with self-adhesive
labels that clearly identify the trial code, the patient number, the patient initials, and the visit
number. The first tube (the primary sample) must be filled with at least 1 mL of serum. lf
only 1 mL or less is available, only one cryotube is to be used. Any remaining serum will be
transfered to additional tubes (the retention samples) at 1.0 rnl per vial. All tubes will be
labeled with the patient study number and date. The serum will be kept frozen at --g0 "C in a
secure, locked freezer. The sample location will be recorded in the lab database. Refer to
the Laboratory Manual for detailed instructions.
PBMC samples: cPT tubes will be processed to yield peripheral blood mononuclear cells
(PBMC) in a distinct layer according to established protocol in the Tumor lmmunology
Laboratory. After collection and washing of the PBMC layer, cells will be counted, frozen,
39 Jull' 2015 \rersicrn: -i.0
I

Aotocol: A Phase II single AflD shrc1l' of High-Dose IL-l ancl Ipilinrurmb in patienrs rvirh tluesecrable stage
III and Stage IV Melauorua
Principal Int"estigator, f
and stored in a secured liquid Nitrogen tank. All tubes will be labeled with the patient study
number and date The sample location will be recorded in the lab database. Refer to the
Laboratory Manual for detailed instructions.
Tumor Biopsy: Fresh Tumors will be mechanieally dispersed to yield single cell suspension
according established protocol in the Tumor lmmunology Laboratory. For the analysis of the
melanoma antigen expression and local distribution pattern of immune cells by IHC and
confocal microscopy. tumors will be also embedded in ocT solution and stored at -go.c.
Samples will be stored in the liquid nitrogen freezer. Alternatively, paraffin blocks (preferred)
or 20 unstained sections on adhesive slides from primary tumor andlor metastatic lesions
(preferably both if available) for immunohistochemistry will be sent to the BRS Lab
Laboratory. All tumor samples and/or patient blocks/slides will be labeled with the patient
study number and date. The sample location will be recorded in the lab database. Refer to
Laboratory manual for detailed instructions.
12.3 lmmune Assessment
Determination of systemic immune responses
fhe development of systemic melanoma antigen specific T cell responses will be
determined by dextramer staining using PBMC from patients and healthy donors (validation
controls) separated by Ficoll density gradient centrifugation as described above Dextrarner
Assay. Human peripheral blood can be stained with MHC dextramers for selected
melanoma antigens (MART-l, gp100, and tyrosinase) and controls (cMV, EBV). The
staining procedure uses a CDB antibody together with MHC dextramers (lmmudex). Briefly,
100p| wholebloodistransferredtoa 12x75 mmpolystyrenetesttube. 10ul of theMHC
dextramer is added and mixed with a vortex mixer. The tube is incubates in the dark for 10
minutes. A titrated amount of anti-CD8 antibody (Dako clone DK25) is added and mixed
well. The mixture is incubated at 4'C in the dark for 20 minutes, Next, 2 ml Easylyse
working solution (Dako S2364) is added and the tube incubated for10 minutes. 2 ml 0.0i
molll PBS is added and the tube is centrifuged for 5 minutes at 300 x g and the supernatant
aspirated. The pellet is re-suspended in 0.4 ml PBS and analyzed by flow cytometry. An
example of dextramer staining in the lab for MART-1, gp100, tyrosinase and no peptide
(control) is shown in Figure 2 below.
39 July 2015 Venion: -l.r)

P:ntocol: A Phase II Si[gle turu Shrt11' of High-Dose IL-] and Ipiliruinmb in parienrs u,irh Llu.esec.rable Stase
III a,d Staee I\' \Ielir,or,a 
!r rrrr LrruclElr
Principal hrt'esrigrrol f
rd' 
,d'
De(lriilner AF'r-.A
rent was treated on a vaccine tria
I whole blood was collected for
3/dextramer analysis. fhis shows a
itive response for MART-I
jPatient was treated on a vaCcine tnd
iand whole blood was collected for
iCDS/dextramer analysis. This shows a
negative response for 
gp100
dextramer.
t::)
F
Df
tJ
<j
ISAPE:U1 I 0hr.T
rot 
,1,'
0*:ltrarner AF4:-1i.
'atient was treated on a vaccine tr
nd whole blood was collected t
;D8/dextramer analysis. This shows
egative response for tyrosina:
extramer.
De).tramer &Prl-4.

fi'i,T"i;*.'lf T,:Hi:i[ 
Amr sttrdv of Higli-Dose IL-] ancr rpiri.ru,rab i, parie,*s *.irrr rr,'resectabre srage
Prilcrpal hn-estigaror
I 5&FEJCI I 1
*b
LL
c,
f_)
'atient was treated on a yaccine
whole blood was collected
DSldextramer analysis. fhis shows
control response
and no peptide.
Figure 2' Sample clextlller staining of peripheral blood from a slngle patient treated on an oncorytic
vaccine triar. The flow cytometry derionsirated a ,.positive" r*nni-i'response.
lf samples are available, some or all of the following analyses may also be performed:
Flow Cvtometry Analysis: Phenotypic analysis for subtypes of T cells from tumor such as Tc,
Th and rregs will be analyzed by four color flow cytometry using FACSCaliber on leukocyles
using the following antibodies (BD Biosciences). Flrc conjugated anti-HLA class I and ll.
cD3, cD4, cDB; pE conjugated cD14, cD19, cD25, cD34, cDs6, cD.r52, perforin,
Granzyme B, cD107a, Foxp3; pE-cy5 conjugated cD45 and Apc-conjugated ccRT and
cD62L' For extracellular staining, cells will be incubated for 30 minutes at 4 c with optimal
dilution of each Ab- Additional activation markers will also be evaluated, including HLA-DR,
ICOS and PD-1.
Pl'otocol \:ersion Date: l9 Jtrl1. lQl,5 Verrion: j.f.)
f edran'ipr A.PC-.s,

Principal Iur.esrigaror:
ilffitJ,i.tif-ir|r:ilif *" srdv of Hish-Dose IL'? a*d lpili.rurrrab i. parie*rs w.irh u,uesectable srapre
Th1 cytokines are associated with favorable
responses while Th2 with progressive disease [81-82]. T ceil subtypes are curren.y
characteriaed by their unique cytokine production: for Thl we wiil use rL_zrFN-vi for Th2 we
will use lL-4; for Thl7 we will use tL-17 and for Ts/Treg cells we will use tL-10 and rGF-p
[81-84] The functional characteristics of the T cells will be determined by their cytokine
production profire. and we wiil sort 3 different subtypes: na.ive, memory, Treg based on
surface expression of CD45RA, cD62L, CCR7, cD2shi and cD127 Additional activation
markers may be sought, incruding cD69, cD107a and pD-1.
lndividual cell populations will be sorted and then stimulated with irradiated autotogous or
allogeneic DC pulsed with melanoma antigen peptide mixture for 2 days at 37oc, 5o/o co2.
cells will be phenotyped for the intracellular cytokine productron followed by Golgi plug
(Pharmingen) for 4 hours incubation prior to staining. For each marker, a corresponding
isotype-matched mAb coniugated with the same fluorescent dye will be used as a negative
control' This study will provide the data for dynamic changes of each subset of r cell
populations during the immune responses.
Regulatorv T cells: For the regulatory T cell population analysis, the following antibodies will
be used: Flrc-conjugated anti-cD4, -cD8, PE-conjugated anti-cD25. pE-cy7-conjugated
ccRT and APC-conjugated cD45RA; APC-conjugated anti-cD4, pE-conjugated anti-cD25,
intracellular APC-conjugated anli-Foxp3 and anti_GITR; pE-Cy7_conjugated anti_tL_10 and
cychromeT-conjugated anti-cD152 (all antibodies from BD Bioscience, san Jose, cA or
eBioscience' san Diego' cA). lntracellular expression for Foxp3 will be detected using the
cytofix/cytoperm kit (BD Biosciences), according to the manufacturer's instructions^ MDSC,
defined as cD14+cD11b+HLA-DR-ldim myeloid cells. which are enriched in tumor (our
observation in human melanoma biopsies), will be stained with Flrc-conjugated cD14, pE-
conjugated HLA-DR, Percp-llT3 and Apc-cD1 1b in addition to cD45-pE.6.5.
Treg suppression Assay: Treg cells will be isolated with human cD4+cD25+ Regulatory T
cell lsolation Kit (Miltenyi, # 130-091-301) according to the manufacturer's recommendation.
The purity of the cell population will be confirmed by flow cytometry and typicalty inctudes
85-95o/o for cD4+cD25+ T cells. All suppression assays wrll be performed in g6-well round-
19 July' l0l5 Verrion: j.0

rrT:.,i;ijlf,:ir:[ff[ 'turrr Shrr1l'of Hisli-Dose IL-] anrl lpilinru,rab in parie*ts rvirh Lru.ese*nrire srage
ililfr,il'"::L)inafinalvolumeat2OOtrllwellofDMEM+10o/oheat.
inactivated Fcs (cellGro). The cD4+cD25- ceils and the cD4+cD25 hi r ceils will be
plated at 3^0 x 104 cells/well at ratio of 1:1 - 1:20. lrradiated pBMCs wiil be added to all
wells as APcs at 3'0 x 105/well. on day 6, 0.5 pci of 3H{hymidine (perkinElmer, Boston,
MA) will be added for the final 16 hrs of culture. cells wiil then be harvested on glass fiber
filters and assessed for uptake of the labeled thymidine by liquid scintillation, as described
previously [1J' Th's assay will be lower priority and done whenever sufficient ce,s are
available.
12'4 Determination of the immune response in the tumor microenvironment
: Tumor samples will be stained for
the expression of melanoma antigens and immune cells. ln addition to hematoxylin and
eosin staining, standard IHC using s100, HMB45 and tyrosinase staining will be done. For
confocal microscopy, tumor tissue will be sectioned using a cryostat, sections will be fixed
and incubated with Biotin- or Frrc-conjugated anti-cD4, cDg, cD11c, cD6g, cDg3 (BD
PharMingen), PE-conjugated anti FoxP3 (BD PharMingen). Biotin-stained samples wilt be
then incubated with cy5-coniugated streptavidin (Jackson lmmunoResearch). DApl
(Molecular Probes-lnvitrogen) will be used to stain cell nuclei. lmages will be obtained by
using a confocal microscope.
:ToquantifythefunctionaltumorspecificCD8+
T cells ex vivo' tumor infiltrating T cells will be stained for intracellular cytokine staining in
combinatlon with Hl3-restricted tetramers. The subsets of regulatory cells including Tregs,
Ts' MDSC and cytotoxic effector cD8+cD107a+ T cells will be quantified by flow cytometry.
12.5 $tatistical Analysis of lmmune Responses
Data relating to immune response will be presented as descriptive summary statistics (such
as mean' standard error and g0o/o cl). lmmune response data will be summarized using
number of sub.iects and percentages for categories as recorded as well as for classification
of responder/non-responder. The major objective is first to determine the presence of
activate cD8+ T cells and number of rreg cells. An increase in T cell precursor frequency
greater than two-fold above the baseline is considered positive for tetramer/dextramer
Protocol \rersiol Date: 39 Jul-v l0l5 Verrion: i.0
F

fii::l;*il, 
i,Hlljii:A,u 
shrdv of High'Dose IL-l and lpili,ru,rab i, parie.rs *'irh Lrru.esectabre stage
Princ ipal Iurestigaror
assays will be summarized using the empirical proportions.
with exact 90Yo confidence intervals. ln addition, a linear mixed effects model (treating
patient effect as random) will be used t0 quantify the rise in immune responses (on a log
scale) over time. The inter-assay variability is minimized in these assays by running the pre-
and post-immunization samples at the same time. The intra-assay variability is determined
by running all samples in triplicate or quadruplicate and the C.V has generally been below
20o/o for all assays (range l-2Ao/o).
13. Human SubJects
13.1 Subfectpopulation
This study is open to patients with metastatic melanoma who are 1g years of age or older
and who may have received treatment of completely resected early stage melanoma,
comprising interferon, radiation, or experimental vaccine therapy, and in the metastatic
setting patients can have had treatment such as chemotherapy, immunotherapy (except
prior treatment with lpilimumab or lL-2), and other experimental agent.
13.2 Potentiat Risks
Patients will be receiving high-dose lL-2 and ipilimumab with risk profiles as described in
$ection 'l ' Patients will be asked to provide a tumor sample for analysis from a previous
biopsy which would not involve any physical risks, or if there is melanoma that can be easily
removed by a biopsy in the office, a sample will be taken. This biopsy is optional. Blood will
be drawn for routine care and laboratory analysis associated with this protocol. There is a
risk of discomfort, bruising and bleeding wrth the blood draws. patients will also undergo
imaging scans to detennine the extent of their disease and their response to treatment that
as part of their routine care. The risk of breach of confidentiality is minimal.
1 3.3 Consent Procedures
lnformed consent must be obtained prior to commencrng any research procedures. The pl
shall seek such consent only under such circumstances that provide the prospective patient
opportunity to consider whether or not to participate and that minimizes the possibility of
coercion or undue influence. The information given to the patient, or the representative,
shall be in a language understandable to the subject or representative. The informed
consent document may not include any exculpatory language through which the subject or
representative is made to waive any of the subject's legal rights or releases, or appears to
release the investigator, the sponsor or the institution from liability for negligence.

Plotocol: A Plrase II Single Aflu Shrcll' of High-Dose IL-l and Ipilinuuuab in parienrs rt-ith tlrue:egable Srage
iII and Stage I\,'\lelauoura
Principal In'esrignror, f
13.4 PotentialBenefits
It is possible that treatment with the combination of rL-2
therapeutic benefit. no benefit, or cause harm to the patient.
for benefit to patients who participate in this study.
and ipilimumab will have a
Therefore, there is a potential
13.5 Risk-BenefitRatio
Based on previous trials of lL-2 and ipilimumab, the NCI suggests that the combination is
feasible and may be associated with meaningful therapeutic responses with a comparable
rate of autoimmune toxicity. This clinical trial will be designed to better define the optimat
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 comparable to and possibly better than alternative options.
13.6 Gender and Minorities
No person shall, on the grounds of race, color, or national origin, be excluded from
participation in, or be denied the benefits of, enrollment in this protocol.
14. Economic/FinancialConsiderations
This study is sponsored by Rutgers Cancer lnstitute of New Jersey with support from Bristol-
Myers Squibb.
15. Publication of Research Findings
The policies and procedures of Rutgers Unrversity's legal department (see: lnvestigator,s
Handbook) will govern publication of the trial. lt is expected that the results of this trial wilt
be submrtted for publication in a timely manner following the conclusion. The cancer
lnstitute of New Jersey Pl, and all co-authors prior to submission or use, and designated
BMS staff must review any abstract or manuscript.
?9 July 2015 Verrion: _1.0

ffij:i1;iJlT:i,:,::* 'tuur shr.l1'orHigh'Dose IL-l ancl tprli,uu*rab i, patie*ts rvirh Lrru'erectnbre srage
Principal Ir.'*srigaror, f
APPENDIX 1
LIST OF ABBREVIATIONS
Abbreviation
ferm
qNc
Absolute Neulrophil Count
3rD
Iwice a Day
BMS
3ristol-Myers Squibb Company
T scan
)omputed Axial Tomography scan
BC
)omplete Blood Count
]R
)omplete Response
]LT
fose Limiting Toxicity
)SMB
lata Safety Monitoring Board
COG PS
iastern Cooperative Oncology Group performance Status
{IPAA
lealth lnsurance Portability and Accountability Act
RB
nstilutional Review Board
rRC
mmune related response criteria
URI
$gnetrc Resonance lmaging
nWHO
Modified World Health Organization response criteria
rD
)rogressive Disease
}FS
)rogression Free Survival
3O
3y Mouth
)R
trartial Response
]D
Cnce Daily
XoL
Suality Of Life
RECIST
lesponse Evaluation Criteria ln Solid Tumors
SAE
ierious Adverse Event
SPD
Sum of the products diameters
SD
Stable Disease
l'NM Staging
umor. Node and Metastasis Staging
IA
fumor assessment
lrolgcol Version Date: 19 Julv
F
?015 \:ersion: i.0

P-rotoc-ol: A Phase II single Anll shld)* of High-Dose IL-l ancl Ipilinrunrab in patienrs vr,ith uruese6able srage
III ald Stage IV Xtelanonn
'ffi 
*ffi) 
RE.'MMENDAT'NS FoR TMMUNE-RELATED
I
I
&snar.a.l r,sr.c1sfrrrrr}&{}r*w*}w *wr rrtam.afr[srrN6{:r( sf,
s tJ&pe* t e*i i *v*rmu.r-re rs*r*txd,*$t*e*,*e * h/e,mt&
S 
{1.5 
!i
il
i r ,tltit.;;: i;i
t,:I

Ptotocol: A Phase u sinsle Amr Shrdl'of High-Dose IL-l nnrl Ipilinrunrab in parierirs u,irh tlruesectalrle stage
IlI and Stage I\' \lehuroum
Princ ipal Ir,r."srigaror, f
APPENDIX 3 
SUGGESTED WORK.UP AND TREATMENT FOR IMMUNE.
RELATED ADVERSE EVENTS (IRAES}
An IRAE is defined as an adverse event of unknown etiology, associated with drug exposure
and is consistent with an immune phenomenon. Efforis should be made to rule out
neoplastic' infectious' metabolic, toxin or other etiologic causes prior to labeling an adverse
event a non-dermatologic, immune-mediated evu-nt, serological, immunological, and
histological (biopsy) data should be used to support the diagnosis of an immune-mediated
toxicity' Documentation of test results should be included in the patient,s medical record.
Gastrointestinal (diarrhea) and skin (rash)-related toxicities have been the most common
IRAEs noted in prior studies with ipilimumab. suggested work-up procedures for suspected
IRAEs of the gastrointestinal traci, liver, skin, el[, pituitary, and adrenal gland are listed
below When symptomatic therapy is inadequate or inappropriate, an IRAE should be
treated with steroids according to the recommended guidelines for ipilimumab toxicity.
Gastrointestinal rract: Diarrhea (defined as either first watery stool, or increase in
frequency 50o/o above. baseline with urgency or nocturnal bowel movement, or bloody stool)
should be further evaluated and infectLus or alternate etiologies ruled out. patients should
be advised to inform the investigator if any diarrhea occurs, even if it is mild. An algorithm for
working up patients with diarrhea or suspected colitis is provided in Appendix 4.
lf the event is of significant duration or magnitude or is associated with signs of systemic
inflammation or acute phase reactants (e.g., increased cRp or prateret count; or bandemia),
it is recommended that-sigmoidoscopy (or colonoscopy, ii appropriate) with colonic biopsy
with 3 to 5 specimens for standard paraffin block be performed. lf possible, 1 to Z biopsy
specimens should be snap frozen and stored. All patients with confirmed colitis should also
have an optholmological examination, including a'slitlamp exarn, to rule out uveitis. fests
should also be performed for wBCs and for stoor carproteciin.
Patients with colitis should discontinue any non-steroidal anti-inflammatory medications or
any other medications known to exacerbate colitis symptoms. lnvestigators should use their
clinicaljudgment as to whether corticosteroids are necessary to treat colitis associated with
ipilimumab therapy and as to what dose should be used. As guidance prior experience
suggests that colitis manifested as l Grade 3 diarrhea requires corticosteroid treatment. For
severe symptoms, prednisone 60 mg or equivalent may be required to control initial
symptoms and the dose should be gradually tapered over at least one month in duration.
Lower doses of prednisone may be considered for less severe cases of colitis. lt is
suggested that prednisone (for oral administration) or solumedrol (for intravenous
administration) be corticosteroid of choice in the treatment of colitis.
Liver: Elevation of LFTs i 3 fold frorn baseline should instigate an investigation into the
underlying etiology for suspected lRAEs. Neoplastic. concurrent medications, virat hepatitis,
and toxic etiologies should be considered and addressed, as appropriate. lmaging of the
liver. gall bladder, and bile duct should be performed to rule out neoplastic or other causes
for the increased LFrs, An ANA, pANCA, and anti-smooth muscle antibody tesi should be
performed if an autoimmule etiology is considered. Consultation with a hepatologist is
appropriate for a suspected liver IRAE and a biopsy should be considered.
Patients presenting with_nght upper-quadrant abdominal pain andlor unexplained nausea or
vomiting should have LFTs performed irnmediately and reviewed before administering the
39 Jrd-v 2015 \:ersion: -j.{)

ir'ijiit,;tii{.*;ti::[ *'" snrc{1'of Hixh-Dose IL-r ancl lpilin*,,ab i, parie.rs u,irh L]ru.esectatrle srage
Priucipal lrr.t"e.rign tor, f
1"-Il9?* of.sjldv dl1g, il""ting physicians shoutd discuss. with rhe study pl, unexptained
lncreases in LFTs.: 3 fold from baseline prior to any aooitionar study drug administration.
Pancreas: symptoms of abdominal pain associated with elevations of amylase and lipase,
suggestive of pancreatllll, rnrv rarely be associated with anti-crLA-4 monoclonat antibody
administration' The differential diagnosis of acute abdominal pain should include
pancreatitis. Appropriate workup should include serurn ,*viru* and lipase tests.
skin: A dermatologist should evaluate persistent and/or severe rash or pruritus. A biopsy
should be performed if appropriate and if possible, photos of the rash should also be
obtained. Low-grade ipilimumab mediated rash and pruritui IRAEs have been treated with
symptomatic therapy (e.9., antihtstamines). Topical or parenteral corticosteroids may be
required for more severe symptoms. The current guidelines for dealing with skin toxicities
related to ipilimumab should be followed.
Eye: An ophthalmologist should evaluate visual complaints with examination of the
conjunctiva, anterior and posterior chambers and retrna, visual field testing and an
electroretinogram should also be performed. Patients with ipilirnumab related uveitis or
episcleritis have been treated with topical corticosteroio eye'drops.
Endocrine: Patrents with unexplained symptoms such as fatigue, myalgias, impotence,
m91]at status changes, or constipation stioulo be investignted for the presence of thyroid,
pituitary or adrenal endocrinopathies. An enoocrinotoiLi srrouto be consulted if an
endocrinopathy is suspected. TSH and free T4 levels sliould be obtained to determine if
thyroid abnormalities are present. TSH, prolactin and a morning cortisol level will help to
differentiate primary adrenal insufficiency from primary pituitad insumciency. Appropriate
hormone replacement therapy should be instituted ir an Lnoocrinopathy is documented.
Neuropathy: Patients should be monitored for symptoms of motor or sensory neuropathy
such as unilateral or bilateral weakness, sensory alterations, or paresthesias. permanenly
discontinue YERVOY (ipilimumab injection) in patients with severe neuropathy (interfering
with daily activities) such as Guillain- Barr6-tike syndromes. lnstitute medical intervention as
appropriate for management of severe neuropathy. Consider initration of systemic
corticosteroids at a dose of 1 to 2 mglkglday preonisone or equivalent for severe
neuropathies' Withhold YERVOY lipilimumab injectron) dosing in patlents with moderate
neuropathy (not interfering with daily activities).
suspected irAEs should be documented in the patient's medical record.
39 July 2015 Venion: J.0

Protocol: A Pliase II sillgle Arlr Shrcl1'of Hieir-Dose IL-l ancl Ipilinrruuab in parienrs u,irh Liru.ese*atrle srage
III and Srlge I\. i.lelanorua
Principal hrr esrignror, f
APPENDIX 4 
DIARRHEA MANAGEMENT ALGORITHM
J..i f..-r-ttrl
1,1
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i.:
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,'I
Protosol \:ersiou Date: 19 July ?015 \:errir:u: -i.0
F
IGRADE 1
lncrease of < 4
stools per day
over baseline;
mild increase in
ostomy outpul
compared with
baseline
IGRADE 2
Illncrease of 4-t
lstoots per day ovet
lbaseline: lV fluids
indicated < 24 hrs,
moderate increase
in ostomy outpul
compared la
baseline; nol
interfering with
ADL
IGRADE 3
I
ilncrease of _. 7 stoots
per day over baseline
incontinence; lV fluids
:24 
hrs;
hospitalization, severe
increase in ostomy
output compared to
baseline; interfering
with ADL
G RADE 4
Life-
threatening
consequenc
es 
(e.9.,
hemodyna
mic
:ollapse)
PRADE 
5
Death

situation: rising liver function tests (LFTs) > 8X uLN or suspected immune-mediated
hepatitis. No mention of Bilirubin levels- what about the side effeci of rL-2?)
1^ Admit subject to hospital for evaluation and close monitoring
2' Stop further ipilimumab dosing until hepatotoxicity is resolved. Consider permanent
discontinuation of ipilimumab per protocol (section o.i.s of protocol)
3. Start at least 120 mg methylprednisolone sodium succinate per day. given lV as a
single or divided dose
4. Check liver laboratory test values (LFTs, T-bilirubin) daily until stable or showing
signs of improvemenl for at least 3 consecutive days
5' lf no decrease in LFTs after 3 days or rebound hepatitis occurs despite treatment
with corticosteroids, then add mycophenolate mofetil rgi AfO per institutionaiguiOetines
for immunosuppression of liver transplants (supportive treatment as required,-including
prophylaxis for opportunistic infections per institutional guidetines )
6 lf no improvement afier 5 to 7 days, consider adding 0.10 to 0.15 mg/kglday of
tacrolimus (trough tevet 5-20 ng/ml)
7. lf -target trough level is achieved with tacrolimus but no improvement is observed
after 5 to 7 days, consider infliximab, 5 mg/kg, once
I' Continue to check LFTs daily for at least 2 weeks to monitor sustained response to
treatment
A flow chart of the algorithm is depicted in the following page.
[otoc-ol: A Phase II Siugle AnI Strrdy of High-Dose IL-? and Ipilirr urrab in parielrs *.ith Lrruerectable stage
III and Stage IV Melanorua
Princ ipal Iu,.'etrignror, f
APPENDIX 5
HEPATOTOXICITY MANAGEMENT ALGORITHM
39 July 2015 Verrion: 1.0

il",i::,1;*.ti" i,:ffi: 
'turrt shrd-v of Higir'Dose IL-l nnrl lpilinru*rab i, patie'rs r'ith rrru'ese.ralrre srage
Prilcipal In\-esrigarorl
: 
Hepatotoxicig Managemont Algorithm
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P|otocol: A Phase II Single -fu'ru Strtd.v of High-Dose IL-1. an<t Ipilinnuuab in Parients u,irlr tlluesectable Stase
III and Stage IY lr{elauonla
Prilcipal Iut'"trigntor, f
APPENDIX 6
ENDOCRINOPATHY MANAGEMENT ALGORITHM
Endocrinopathy managsment algorithm
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ll i,r(lru$l;,,lrt hr'! |l.j
ll1 , Bplr.irr :r r r {r{lrpl, iJts( (}nltnL;,ilr.N o'
1, t,.n.,,,r,. :{,r' I ;)rt,J,j:1Jr{! .}lr'.,,ir
l$wrf:{f9 $rilf
i.*r8tx}!!i
'1. Rul6 out eepsl$
?" ll strong sospicion ol edron{t cri$i3 (sg. sxhibils
iign* bf sey$r6 dehydfation . hypolrn$ion, o.
$hocl out of progoallon to $dvorlg ol eurant
lllness) then $lsrt 6tr8is doBs lV it€.old* (with
id 6ctivlly ), ttuids. corlsult
$t
3. lf symploms $,ugg€$tivr ot endorrinoprthy but
i6 .rol in crisi6 ttBn it may b€ ,ppropriat* to
fsr lab re$ults br{orG $lsatinE stsrold
?9 Jul-v l0I5 Version: -l.t)
Y$.s
Pi'otocol Versiou Date:
T
Paee 99
Ni:

riifi1,*.'l[-i,:,;:::: ** Sttrc{1'of Hish'Dose IL-3 ancl Ipirinrunnb in parienrs rvlh Lrru.ese*abre srage
Principal hn'errigator: f
SUBJECT REGISTRATION FORM
cA-t_94:09_4
Protocol Number:
lnvestigator ldentification
lnstitution and affiliate name
lnvestigator's name
lnvestigator phone
Patient ldentification
Patient's initials (Last, First)
Registration number
Patient demographics
Sex
F
M
Birth date (mm/yyyy)
Race
Ethnicity
Prior therapy
lnformed Consent
Subject signed date (mm/ddtyyyy)
Please attach a copy of the signed
3,ololol !'ersiou Date: 19 Jull'1015 \:ersion: -j.fl
#
consent document to this form.
Pathology
Please attach a copy of the original pathology report to this form
PLEASE NOTE THAT SUBJECTS MUST MEET ALL OF THE ELIGIBILITY
REQUIRMENTS LISTED IN SECTION 4.0 OF THE CLINICAL PROTOCOL

Ptntocol: A Phase II Single Amr Snrd-r- of High-Dose IL-l antl Ipiliruurrnb in Patients rvith Lftu'esecrable Srage
III and Staee I\i llelanonra
Prilcipal Iiresrigoror, f
Please note that blood and tumor specimens must be submitted as detailed in
Section 12 of the clinical protocol and using the SPECIMEN SUBMISSION FORM
located in the Laboratory Manual.
Protocol Number:
SUBJECT ELIGIBILITY CHECKLIST
cA184-094
Title: A Phase II Single Amr Strrdy of High-Dose IL-2 aud Ipilinnunab iu Patients with
Uuesectal,:le Stage III and Stage I\.'N.{elauorna
Protocol Version Dste: 03 Oct 2014
Protocol Number: CA184-084
lnvesti gator ldentification
lnstitution and Affiliate name:
lnvestigator's Name:
hon
nve
ator
e
Participant Naure: (Print First aud Last)
Patient IWRS Screeuirrg Nrunber:
Attending; ( Print First and Last)
Consenfiug Prot'essional : (Print First and
Last)
Registering Lrdir.rdual: (Print Frst anrl Last)
Registeriug hrdir.idual Phone Nurnl:er:
f)ate of Cornent:
Clonsent Ouestions:
1.0
Is the parricipaut tluent in English'? (Yes.No)
IlYes. .skip tct the Eligibilitr Critet'irr sectian; if Nio, continue u,iilt
Corrcent Quesliatt 2.0
:0
\Vhat is the participant's primary
languaee?
3.0
Was an IRB-approved tratslated intbmred consent usecl in the
parl icipant' s or legal [_l- a uthorrzed represeula tive' s primar-v lan gua ge
?{YESNO)
Protocol \iersiou Date: 19 July 2015 \:er'*ion: J.0
r
Page l0l

Principal Lx'ertigator:
,1.0
\Yas an lRB-approved shorl-lhru gi!'en ro the pafiicipalt or legally
authorized replesentative in their priruar.v lauguage'? (YESNO or
NA)
5.0
Was the lRB-approved English conseut ol'sununary.sigurecl [:y the
consentilg professional? (YesNo,t JA)
60
Was au iuterpreter (nnn-thmily rneruber or caregiver') used for the
discussion? (YES,t{o,,'NA)
Protocol: A Phase II Single Ar:n Shrdy of Higlr-Dose IL-3 and Ipiliutulmb in Patients rvirlr Lkresectable Srage
III and Stage IV Melauoura
The subject must meet the following criteria to be eligible for the triat (please check):
E
ERIA:
1.0
Horv old is the patrent'? (..
_l_
l8 \.es of age) DOB:
R*ce (Mrrst circle ATLEAST one choice):
Arnerican Indiarv'Alaskan Natir,e
Asian
Black,Ah'icarr Amerrcan
\tr'hite
Native Hawaiiaryother Pacific Islalder
fthuicity&.Irrst circle AT LEAST oue choice):
Hispanic
Non Hispanic
Gender: \{,F
2.0
Does the patient have histologically or cvtologicallv
cont-rmrecl diagnosis of cutaneous melanouta that is
considered uuesectable (Stage III or IV) ? (YES,}(O)
Stage : T:_N:
M
(Note: stage at study start)
Date of Initial Diagnosis: I 
I
la.
Does the patierrt have Ocular ot lv{ucosal melanoma'J
(No)
"1.0
Does tlre patient have measurable disease that is at
least 20luu b.v CT scan or:,10 nun fbr spiral C'T
accordiug to REC'IST and WHO (rn\\lHC))
l) (Yes)
Protocol \:ersittu Date: l9 Juh, l(]15 \rersion: .i.0

Ptotocol: A Phase II Single .\'ru Shrdy of High-Dose IL-l ancl Ipil.irrruuab in Parienrs .n'irh Llruesee-ratrle Staee
III and Stage IV lvtelanoum
I hrvestigator
_50
Is the patient's life expectancy i 3 uronths? (Yes)
60
Wbat is tbe patient's ECOG perfonnance staftrs? (0 or
l)
Date: r' 
/
7.0
Is the 1:atiertt ar:cessible and able to cotnpl): lvith
lrealrrreut. PK ancl irrurnure-r urrnitor i ns sarrrple
collectiou. ancl required snrdv tollorv-up? (Yes)
8.0
If the patieut is a rvoman of childbearing poterrtial
(WOCBP)- does she have a negative sellrol or tuine
plegrancy test (uriniulun sensiti\rity 1.5 UI/L or
equivalent units r:f HCG) rvithin T2 horus trefr:re the
start of ipiliruuurab. or Dav l. rvhich is acceptable per
the sptrrxor'? (Yesl NA- only if the patieut is rnale r:r
not of child bearing poteutial)
Date: 
i 
;
If the womail is a woulel of lri0N-childbeanng
potential . please give reason for stahm:
o Posl -meuopalrsal f)ate of last urenstnral
Period: 
-l_
Hvsterectorrry andl'or o0phot'ectorttv Date of
sruger\': _,__ 
_
Other: Please explain.
,,\role.' N o n -c h i I d b e a ri n g p o I e n t i s I i s d eJi n e cl
rl.f.'
Il.vstelectourv . bilate'ral tubal ligatiou. or
bilateral oophorec tt'rnrY
Anrenon"hea ., I f cousecutir.e ruonths rvithout
another cause and docruueuted sellult tbllicle
stirnr"rlating horlr. one GSH) level,,40 urfUinl
Inegulzu' ureustnml periods aucl a drx-tunented
serum follicle stirnulating honnt'me (FSH)
ler.el .,.10 mfllrml and Receivrng homroue
replaceurent therapy {HRT)
,\role: FSH leyel testing is not required for
xron en > 62 lsors old wilh amenorrhea of > I
yeor.
Protocol Versrou Date
r
Page I Cl3
39 Jrili'2015 \:erslon: -i.0

Priucipal Lr.,.esligaior
9t)
If the patienl is a WOC'BP. does she agree to use au
acceptairle urethocl of cr-rntraceptiou tc' avoid
pregnancy tluoughout tlre strrcly and for at least 4
rveeks prior to iuitiation of clmg and tbl at least 26
\veeks atler the lasf tlose of investigatioual product iu
such a lnruner thaf tlre risk of pregualcy is
ruinirnized'? (Yesi NA *oul.v if the patient is male or
not of childbearing poterrtial)
t0.0
If the patient is a sexrmlll.'actirre nrale, does he agree
to use an acceptable nrefhocl of contraceptiou
tluoughout the shrdy and tbr a{ least 4 rveek,s prit'rr to
initiatiou of the dmg and tirr at least 8 rveeks aiier the
last dose ofurvestigational product iu such a [uuu]er
that the risk of preguilllcy is rniuiurized? 1Yes,$iA-
ouly if ths patient is a female)
I 1.0
Is the patieut preenaut or trreastt'eedilg? (Nr:/NA-only
if the patieut is a rnale)
12.0
Does the patierrt have lororvn or srmpected braiu
uetastasis? (Yes'tio)
13.0
If Yes to 12.0, have the brain metaslases been
previousl_v treated'? (Yes${A- ouly if the arr.srver to
euestior 1,1.0 is No)
140
If Yes to 12.0, has an N.'{RI rvith and witirout cc}utrast
or CT of the brain been perfbnned to nrle out [:r'aiu
uretastases or lo show no evideuce ofprogression for
at least 4 r.r,eeks? (Yes1}.{A-only if the answer to
questioll 14.0 is No)
15.0
If Yes to 12.0. has the patient been otf
irrumurosuppressive doses of systemic rnedicatiorr. at
least 4 weeks at tiure of elu'olhuent'? (YesNA-ouly if
arslver to question 14,0 is No)
Note: Corticosteroids have a washout period of l4
davs prior to randourizatir"ru.
16 0
Does the palieul have prior nraliguancv active i.vith the
previr:us -i 1,ears? (No)
Protocol: A Phase II Siugle Amr Shrdy of High"Dose IL-3 and lpilimuurab in Palients rvith Lkuerectable Stage
III and Stage IV Melatroun
Protocol Versiol Date
Pnge I f,l1
29 Jull' 30 I 5 Version: i.f.)

Principal In.,'ertigator
17.0
Does the pfltient have. arry aclive auloillunrule clisease
or a docruuented historv of autoinuruure disease'l (No)
18 0
Does the patierrt ha,",e a historl" of a sl.ndroure that
required svsteuic steroid ol iuulurosuppressive
medications'l (No)
Note: Subject rvith vitiligo . psodasis ir active r.vithiri
tire past 2 years . resolved cliildhood asllurlfli'atoph.v .
or thyroid disease controlled by rcplaceureut therapy
rvitltout tlre need for inununosuppressiou are eligible
190
Does the pafielrt have known or srupectecllrumau
inunne deficiency t inrs (HI\i) . hepatitis B or C
itfection? (No)
100
Does the patient have or a histoly of extensive
pulmonary ruetastases or clur:nic ptduotary clisease
bistory? gt{o)
Date: i 
!
l.lote: FE\:1 and FVC' :r (1\0,-
Note: Onh,'fcrr patieuts rvith pulmonary function:
FEV1 and FVC > 6501, of prediction for those patients
with extensive pulmonary metastases or chronic
p qlm o_n_a ry_$ipeqs_ e_ hptgry_,
l:.0
Is the patierrt on beta-blockers'J (Yes..No)
Note: Patieflts nmt: be wearrcd affo/beta-blockers fiw
weeks prior to sfidy eilrollntent wder the xtperuision
_{ "tl : gzu :t19,}_t a y!!o lggi s I
:30
Does the pafient have an urderlving heart couclition
and those 50 r'earc or olcler rvho have reversible
ischemic changes on cardiac stress test rvho are
deemed ineligible for sru'gerv by caldiolog.v consult?
0ro)
Date of Caldiac Stress Test: 
i 
I
24.0
Has the patient treet treated with IL-3. ipilirnurnab or
prior C'TLA-4 inhibitor or agonist? (YesNo)
Note: not lbr rnetastatic disease.
25.0
If 1'es to 26.0. has it been at least 6 nrt-rnths since the
final acljur.ant treatrrlent tlour start of studv treatmerrt'J
Plotocol: A Plrase II Siugle Anrr Study of Higlr-Dose IL-!, ancl Ipilinuuuab in Patienrs wiih Uruerectable Stage
III and Stage IV Nlelauorna
Protocol Versiou Date: 19 Jull'1015 Versinn: -i.0

horocol: A Phase II Siflgle .A,nu Shrdy of Higlr-Dose IL-3 ancl Ipiliuunrab in patients rrirh Lrruese6able Stagre
III ald Stage IV N{elanorua
Principal hn'esrigaror:
(Yes,tlA only if answered NO to 26.0)
Date: 
I 
i
260
If ves to 26.0 did the patient have Grade ,l or greater
adverse e\reuts tvith prior adjuvaut ipilimuurab therapl-
that did not resolr.e ivith linritecl corticosteroicl use,l
(Noi NA onl.v if arisrverecl N0 to 26.0)
:7.0
Does the patient har.e presence of au uncterlying
rnedical conditiou that il the opirriou of the
investigatot'or Spoffior could adversel) affbct the
abilitl,- of the sutrject to compl)'rvith r:r tolerate studv
procedtues and,or snrd-v therapy' :) (1r{o)
28.0
Does the patient have et ideuce of organ clysfiurction
or arlv clinicalh- signiticant derrintiou tr.our lonnal in
phvsical exarrfrratiorr. vital signs. ECCi or cliuical
latrnratory deterlrinatiorrs trevoutl rvha t is consistent
rvith the target populntion? fir{o)
29.0
Has the patient been treated rvith s,vsternic auti-caucer
treatment (includiug itrvestigation dnrgs ) rvithin 4
rveeks of tu'st dose of stucly iledication? (No)
Date of Last Treatnrent: I 
i
Has the fiai;,,t bd; tr;;64 '-1iililiid;*ipp;.;F
rnedications or irununosuppressir.e doses of s1..stenilc
coflicosteroids (doses :,. l0 urg/dcav predlrsone or
equivalentJ r.vithirr l4 days of t-rrst dose of shrdy
uredication? (l-lo)
30.0
33.0
Did the patient har.e sulger_v or radiotherapv rvithin 4
rveeks prior to emolhneut rvithout anv sequelae of the
errollnreut of stuclv ureclicatiou'l (No.1
330
Did the patierlt have any non-oucolog-v- live viral
vaccine therapies used tirr preventiou of ilrtbctious
clisease rvithin I month of the fir.st dose of snrdv
ruedication? (No-)
3.{.0
Dicl the patient har,.e prior treatruent rvith lpiliniurnal:
!rytocol \rersiou Dare: J9 Jul1, ?015 \renion: .i.0
#

Protocol: A Phase II Single Anu Shrdy of High-Dose IL-3 and Ipilirrrumab irr Patielts u'ith tlru.esectable Srapre
III and Stage IV lvlelanorua
Principal Inr"esrigator:
oI IL-?? (No)
35.0
FIas the patieut been treated rvith auti-CTLA A'l $o)
360
Is the patierrt a prisoner or invohurtarilv incarceratecl?
(Nc,)
370
Is the patienl ct>lt1>ulsorilv cletainerl fbr treaturent of
either a ps).chiatric or phy$icfll (e g . iufbctious
disease) illrress'l (No)
38.0
What is the patients ANC? (:," 1000/uL)
Date: --i=-/-*_--
-39 0
What is lhc'patiell's pia(elet count? ( :," 75^000 hL)
Date: 
-- 
--'*-
Note: Tronsfusiort lo achiele the requirecl leyels
respectively, is not permifled.
40.0
What is lhe patient's Hernoglobin? (> 9.0 gldl,)
Date: _i_r_
Ne!g; P- 80 g/L; moy be trsnsfased)
,11.0
What is the patient's total creatiniue'l (S:.0 x ULN)
Date:_ 
i_
:1:.0
What is the patient's total bilinrbin? (S 2.0 x LILN )
Date: _
Does have patient Gilbert's Sytdrorne? (Yes.{.{o)
Note: patients rvith Gilbert's Syrdroute. rvho orrmt
have a total bilinrbin less than 3.0 mg/dl-)
.t,j.0
\*'hat is the patierx's AST? (r 2.5 x ULN fbr patients
without lir.er nreta.slasis.
5 5 times tor patients with liver uretastases)
Date: I 
i
4d0
What is the patiert's ALT? (::.S x ULN fbr patients
rvitlrout liver uretastasis.
< 5 times fi:r patients rvith liver rnetastases)
Date: i 
i
450
Is the patient rvilling and atile to 1:r'ovicle sigued
infonned couseut. including conseul l'or an_v- screeuinq
procedrues corrrhrcted tn estaLrlish eligibilin' for
registratiou. requirecl prior to trial particiliatiou'l (\'es)
Protocol Versitll l):l te
r
Page 107
19 Julr, 2015 Verrion: ,i.i)

Plotocol: A Phase II Sing.le ,turu Shrdy of High-Dore IL-l and lpilimunrab irr Patients u,ith tltuerectal-rle Stage
III and Stase IY X{elauoura
Principal ilr"e*tigator: f
Team
Ph
ician ur ('onseutin
Professional
By signing above I attest that I have rer.ierved and cont-rnned that the abr:ve eligibility has
beeu uret
Reviewed and Approved by ; (Print First and
Last Narue)
Rer.ierved ald Approvecl by. (Signttule)
Title:
tion
E
Registrntion will be performed b,v Theradex's I\I.,RS Svstem
tt
Patient Identifi catir:n
Patient's iuitrals llast. First)
IWRS Screeilins Nruuber
Pre-Treatment Evaluation :
TO BE COMPLETED WITHI){ I }IOI{THY OT' STI DI'
DRTiG AD}IINI STRdTIOI{
1.0
hrtonned C'on.senl
I
I
2.0
N{edical Hislor_v including toxicities or allerg.v telated to
previous treatrnerts
3.0
ECOG Perfiuruance Statrts
d.0
Courplete Phvsica l Exarttina tiott
5.0
Conconritaut N,ledication Revierv (Checking tbr protocol-
excluclecl medications )
I
6.0
C'linicaI Coutplaiuts au<l Aclverse Events
7.0
CT/N'IRI of chest. abdotnen and pelvis {u,'u o corrrrast)
8.0
Cardiac Stress Test
9.0
10.0
Pulnronarn Frurctiou Test{ if needed)
Date: 
/ 
/

Pr"otocol: A Phase II Single Arur Shrdy of Higlr_Dose
III and Srage I\,'lvlelanotna
IL-? and Ipiliruurrrab in Parients rl.irh Liruesecratrle Stase
D \YITIIING 2 \\'EEIT
AD}III{STR,{TION
Fresh Truuor Biopsl, {optional
Biocherrristry.-Ele
chlolide arril ulagrresiulrl. ser.ulrr ..*.lirr". BUN)
Phosphorous
ALT,A S TALP. Tota I B i linrtr i,ilH.p.t". ft ,". rr-
.Heuratolog_v(CBC' rv j DiiTerentia I . nia tel er s )
T3.TSH.T.{.
ll- Leacl EC'Ci
Senuu Protein
Albunriu
LIt'irri,rlvsis
Vital Signs
Terrrp:_BP:
Rate:_:
Respiratory Rate: 
Hearl
:\L eislrt:
Preglancl
"-llge;.Day
Test (Senuu)-
I isOK
Protocol Ver..sir:l Dale
Pase iDE
?9 July 2015 \,'ersiou: j.0
LDH
tt

prorocol: A plrase II Single Anu Shrel1,of Higli-Doie IL-l ancl Ipilinruurab in Patients u,ith L&uesectable Staee
III and Staee I\' \lelanoma
Pri,cipal hr.'esrigaror:I 
oFr sruDy F,RM
Protocol Number: A Phase II Single Arm Stutlv of High-Dose IL2 nnd lpilimum:rb
in Patients rlith ['nreseclrrble stage III and Stage I\' ]Ielanomr.
I 
I
lnvesti gator ldentification
lnstitution and affiliate name
Investigators name
Patient ldentification
Patient's initials (Last, First)
Registration number
Date Subject is Off Study (mm/ddlyyyy)
Reason Subject is Off Study:
tt
lnvestigator Name (print)
Signature of lnvestigator Name
best response achieved; date
progressive disease; date
toxicity; describe
lost to follow-up
physician preference
patient withdrawal, reason
patient never received tx; reason
other: describe
Date

Protocol: A Phase II Single.{'nu Shrdl.of Higlr-Dose IL-l and Ipiliurutuab in Patienrs r.r.ith Llru'esect,lbte Srase
IIi ancl Stage IV \lelanonra
Principal In.'ertigator, f
Protocol Version Date: 29 Jul_v ?til5 \rerrion: i.0
F

ECOG
status table:
Description
Grade
Fully active, able !o carry on all pre-disease performance without restriction
0
Restricted in physically strenuous activity, but arnbulatory and able to carry out
wgLqf a light or sedentary nature, i.e. light housework, office work.
1
Ambulatory and capabte of self-care , but unable to carry out any tork acttr tiea
Up and about more then 50o/o of waking hours.
2
capable of only limited self- care, confined to bed or chair more than 50o/o of
waking hours
3
completely disabled. cannot carry on any self-care. Totally confined to bed or
chair
4
Dead
5
Protocol: A Phase II Single .furtr Shrdv of High-Dose IL-l nncl Ipilinrrurrab in Parients u,ilh tlru'esecfable Stage
IlI and Stage I\'\{elanoma
Principai Iur".*igotor, f
Karnofsky Performance Status (KPS)to ECOG Conversion Table:
liamo fsxy'- Perfonrranc e S tanx
(D.A. Kanrotiky zurd J.H. Burcbetal^ The clurical evaluatiorr of cheurotherapeutic agrents il cancer hr: C.M.
Ir'lacl-eod. Editor. Eraluatiou of chenrotherapetrtic aglerts in cancel. Cohunbia Uuiversrty Press. Ne*,York
(1949). pp. l9l-2051.
r 
l00o,o- uomral. lo cornplaint*. uo evideuce of disease.
r 
90%- Able to calr1i ou trorrual actir"ir"v.". nriror sigrrs ol's.yrrrptoln of disease.
o 
80016- Nor:nal acriviry u'ith etforr. soure siplrs o[ s,vurtonr-! of disease.
r 
700/o- Clares tbr selt. tunble to cany on nornal actir.i6,or to do u'or.k.
. 
600,6- Reqtrires occasional a.\iii$tance frorn others but able to care t'ot'rnost needs.
I 
50%- Requires considerable assistance fiunr others and frequenl rnedical cale.
r 
,{096- Di:abled. reqrrires special care arrd ar;istzurce^
r 
-10o.'o- Severly disabled. hospitalizatior indicated. death rrot irruninent.
. 
f0qb' Very sir":k. hospitalizaricur necessary. active supportive treahlrent necessiuy.
. 
109.i,- Moriborurd. faral processes proeressiug rapidly.
r 
09.ir-Dead.
KPS
ECOG
100
0
90
1
80
1
7A
2
60
2
50
3
40
3
30
4
20
4
10
4
U
5
Protocol \:ersiou Date: 19 Juh,20l5 \:errion: -1.0
I
Pase I l2

Profocol: A Phase II Single A:u Snrdt, of High-Dose
III aud Stase I\: \.lelmroura
Principal In. ettigntor, f
IL-l ancl Ipilinrruuab in Patiellts rvith tfuu'esectatrle Srage
Tumor Assessment Form:
Rt0sT l.t El.DrMtr{tt0trA. nispon$ ASttSsMEilr rof;M {ur}t0}
ftt$0N[
suMlrEfrY f0r SfsI ovtBAI ntspoftst
Ig$!@lt**n 
raolcrurntlksmm6*bnlrn{&ri}th3k
{on-nodrl m6l !. !D f D nn oiCTl{Rl
rtl.oruroble lynplr aodcr must b. ! f nn io tlE rhort lrh 0r CIIIf,1
dinic.lt nuil h. I D oa $rn nelrwd ilh cdiprrs
ksDmse oft roelhsixrs
0i: 0*gprclrr'o{dtqdiches;fmt'rmdxmx&(0nmslD,ts
P R :Al led 6ffidr8donl't*mol dsrdes
P0 tt lai a$l,lrreae nthsnr ol &dea
SD I'le*sPRrr P0
lfun-TatOet leiO0S ; Alofrbsnr.nlrtqsnolkis6{10 (0flr orE
Resmme ol non.lilqet leskns
CR: Dnppmurt oi r[ mo-trp lcml: ud oamrhttpl of tmoE o*l
llor"Cfllllon"P0. Puxcocc olort or oort loo.tana kur{s) ardtr ue
P0 Proprmol of trr*og oor+r6t lcmo*r*r brnrt
EYalElion of besl ol?rall reslonse
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Protocol Versiol Date: l9 Julv l0l5 \:errion: J.t)

Protocol: A Phase II Single Anu Studl' of Higli-Dose IL-l and lpilinruniab in Palierts u'ith LLuerectable Stage
III and Staee I\: Ilelanoma
Prilcipal Iio.rrig^tor, f
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Protocol Versir:rn Dale: l9 Julr'1015 VerEion: -i.0

Protocol: A Phase II Siugle turn Study of Higlr-Dose IL-3 ancl Ipilinruurab in Parients with Lluesecable Stage
III aucl Stage I\: \{elanoma
Principal hr,'ertigator: f
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Protocol \,'ersion Date: 39 Jrrlv l0l5 \rersion: -i.{)

6.i
66
Protocol: A Phase II Single,A,mr Study of High-Dose IL-3 nncl Ipilinrurrrab in Patierrts u'ith tltu'esectalrle Stage
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Prirc ipal Irirr'"rtigotor, f
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I\.{_vels Squibb Clr:rnpany ancl h,ledare.x Lrc. 1008. Doctuneut (outrol No. 930026869"
CA184008 Clinical Snxly Repofi. A Multicenter. Sitgle Amr Phase ? Shrdy of
N{DX-010 (BN{S73-}016) I!'louotherap-v in Patierrts urith Previousl-v Treated
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Protocol Versiou Date: 19 Jtrly 2015 \rersion: i.0