Trial of Interleukin-2 in Combination With Pembrolizumab for Patients With Unresectable or Metastatic Melanoma
Phase: PHASE2
Conditions: Metastatic Melanoma, Stage III Mucosal Melanoma of the Head and Neck, Stage IIIA Skin Melanoma, Stage IIIB Skin Melanoma, Stage IIIC Skin Melanoma, Stage IV Skin Melanoma, Stage IVA Mucosal Melanoma of the Head and Neck, Stage IVB Mucosal Melanoma of the Head and Neck, Stage IVC Mucosal Melanoma of the Head and Neck
Sponsor: Rutgers, The State University of New Jersey

Official Title:
A Phase 1blllTrial of lnterleukin-2 in Combination With
Pembrolizumab for Patients With Unrespectable or
Metastatic Melanoma
NCT number:
02748564
Document Type:
Protocol- SAP p.74
Date of the
Document:
oel2rl2o2t

***
mrd Lactction fo Merck. If t&ere ir *uy questiou that a subjeet will not reliably eonrply with
the require.uents for contraception, ftrrat subject should not be eutered into the study.
5.7.3 use in Pregnancy
If a subject iuadvertently beeomes pregprant while on treatment with peurbrolianuab, the
subject will irnrnediately be removed ftom the study. The site will cortact the sulrject at leasf
moutHy aud docurnert the zubject's $tntns uutil the pregsarcy has been cor:rpleted or
terminated. The outcome of tbe preggmey will be repor"ted to Merck without delay and urithin
24 hours to the Sponsor *nd within ? working days to Mertk if the outcorue is a serious adverse
experience (e.g., death, abortion, cougenital anarnaly, or other disabling or life'tlureatening
complic*tion to the motlrer or uewborn).
The study iuvestigator will urake evr.ry ettort to obtflio pennisxiou to follow tlre outco&e of
the pregp*ncy sad report the coudition of ths fefus or newbom to the Spousor. If a urale
*,rUj*t impregn*tes his female parfirer the study pereorurel at ftE site must be infomrd
iryuedi*tely and the preg$arcy r*ported to [nd 
followed as described above and in
Section 7.2.5.
5.7..{ I"Ise in Nursing Women
It is unkuawx wlrefher peurbrolizruuab is excreted iu hruuan milk. Since ruany drugs are
excreted iu buman milk, and because of the poteufial for seriorx *dverse reactions in the
uureing infant, sutrjects who are breast-{beding are not eligible for emolhnent.
5.8 Subject WithdrawaUDiscontinucfion Criterio
Subjects rnay withdraw consent Bt aoy tiure for ary reasor or be dropped *om the trial at the
discretion of the iuvestigator should any untoward effect oecur. In addition, a subject may be
wittrrdrawn by the investigator or the Sponsar if,enrollnnent into the trial is imppropriate, the
ki*l plan is violoted" or f'or adxrinisbative and/or other safety ressons. Specilic detsils
regarding discoutinuation or withdrawal are provided iu Sectiou 7-1.6.
A subject urust be disconfinued fium the trial for any of the following reasolls:
r The subject or legal representative (such as a palent or legal guardian) withdraws
consent.
r Coufirmsd radiopaphic dinen*e progre*sion
r Uucoafinned disease progression plus clinical deteriorntion
r Uuacceptable adverse experieuces as judged by the treating invesfigator
e trntercunent illness that preveats further a&nhishatiou of treatment
r Investipmtor's decision to witlrdraw the subject

l[ *omexre*
r The subject has a confinned positive $anuu preprancy test
r }t{oueorupliauce witr uial treatmeut orproce&xere,quiremants
r The subject is lost to fbllow-up
r Completed study treatrnent
r Adminishativereaso[$
The Fcllow+rp proeedr$es flre listed in S*ction 6 (Prutoc.ol Flow Cbnrt) and Section ?"1.5 Visit
R*qlrirernents. After &e end of &eatme&t. each subjact will be followed for 90 days for a verce
eveut monitoring (rerious adverse events will be csllected for 90 days afterthe end of freaiment
as described in Section 7.2.1.1).
Subjefis who discontinue Ibr r6s$ons other lhau progp'essive disease will have past-treafinent
fotlow-up for disease stah$ rmtii disesse propgession. initiatiug a lon-study ca$cer keofinenf,
withdrnwiug corsent or becoming lost to follow-up- ASer documented dixease progres*ion
each subject will be followed by telephone for overall survival urtil death, withdrawal of
cousert, or the eud of &e study" whichever occurs fi*t.
5.9 $ubject Rrplacement Stmttgy
Sulrjects iu the Phsse Ib portion of the study who are not evalunble for toxicity will be replaced.
Subjects iu th* Phase II portioll who are not evaluable for response will be re,pla*ed. See seclion
S.4 for definifion of evaluable for response.
Sixty (60) evaluable subjects will be eccrued. A maximuu of up to 65 patients may be enrolled
(try to 5 replacements). Subjects who are screea failures do uot count towartls accnral.
5.10 Criteris for Early Trial Terminstiou
Early fial temrirmtionwillbe t&e result of the eriteri* specified below:
1. (hulrty or qu**tiff of data recording is iuaccur*te or ircomplcte
2. Poor adherence to protocol and regulatory requilements
3. Incidence or severity of adverse drtg reactioa iri this or other studies indicates a potential
health hazsrd tc subjects
4. Plsns to uodi& or di*contiuue the development of the study drug
Iu the event of Merek decision to no longer strpply study drug. ample notificatiou will be
provided so that appropriate adjushuents to srfiject trealmeut can be urade.

Product: Pturbroliztuu*b
PnotocoUAmmdment No.:
6.0 TnIAL TLOW CIIAA,T
Table 6- Srudy Flow Chnrt
53
?r'lnl Pedodr
$creenllg
Tr*atmenl (\Yeeks)
Safefy
Follot'-u$
Loug-fcrm
Follox-up
Trcaurcrrt (yclclIitk:
Sndy
Scrcarirg
vi*it{i)
Coursc I
I
4
1
t0
12
{90 dny: aftcr
last do*c ofrr)
$urr.irnl
Follow-LTp
Q12 rl'cekr
Coursc !;
13
l6
l9
') ")
l4
Corrsc 3:
:-r
28
JI
34
l6
Corrscr
4-0:
Qr
Q3
Q3
Ql
Ql3
Schcduling Wiadorv (D*p):
-!s*
*t
rt
:h/
*14
*28
Infonned Conscnt
x
lnch&ioL€xclusion Criteria, ilcluding
puhuonary frrnction andcardiae strcss tcstin$
whcr appropriotc
x
Dcuroptphics and btcdical History
x
Prior ard Corrconritant Medicatiou Revicrv
x
x
x
x
x
x
Peiubrolinrnub Adninistrationo
x
x
x
x
IL-3 Adminirmtionb
1b
X!
Rcl"icw Advcrsc Evcnts
x
x
x
x
x
x
Plryric.al Exanrinatiorr9
x
x
x
x
x
x
tr'ital Sigrn and lVcightd
x
x
x
x
X
x
EC0G Pcrfcmraucc Status
x
x
x
x
x
CBC rvith Di&rcuti*I, Cornprehcnsil'c Scnun
Clrcmir*ryPand (D. Eili if T.Bili > ULN).
lvtaErcsirurl Phosphonn.
x
}r
x
x
x
x
Amylasc, ad tipa*c- T3- Frcc T4, T$II. Utic
.{.cid. LD}I!
x
x
x
x
PTilNR aPTT"U,{, CXR, EKd
x
yf
r
Prcgrunry Tcst -Urinc or Srnmr FHCG8
x
x
x
x
Conclative Sfirdics Blood Collcction
yt
Turuor Assersrucnth
x
Twtor Tissue (ollcctioni
x
xr
Port-*rdy disease stshrs .trd mtiss[ecr
ther*py status
x
Strrival Status
x
Footnotes

Product: Pentbroliaunab
ProtoroUAmentlment No.:
* All screening assessruents withirr 28 days of Day I of keahneut, turl*ss otlrcnvise noted.
Brnin MRI for screeniug uray be perfonned qp to 90 days prior to tlre fnxt dose of
trisl heatnreut if ttrrere is uo evideuce of braiu metastsses" Subjects with kuown,
previously treatedbrain metastsses ruayparlicipate provided they are stable (wilhout evideuce
of progression by irunging for at l*ast fox'weeks prior to the fust dose of kial tr:eatrnent a$d
any nerrologic syuptorns lnve retumed to baseline). have no evidence of uew or eularging
bmin metastases, arrd are not usilg steroids for at least 7 days prior to trial treatrnent.
&. Pembrclizumab may be discontiurred for palierrts who lmve achieved a
coufirmed CR and hsve received treatment for 6 nrouths following CR per
Sectiou 5.3"1.4.
b. Concouritaut medicatiots il]u$t be rcviewed prior to each cycle of It-2. A
prophylactic attibiotic, $uch as oxacillin, unxt be administered to plevent
catheter-related infeetions drriug the hospitalization. The follorving should be
done daily drriug IL-2 adrninistration: neuologie as$e$smeut, courplete blood
count. btood chenristries, chesf x-ray, vital sigrrs, ptrlse oxirnetty, weip&{, and
fluid intake and output. In the dose-escslation portion of the shrdy, subjects will
be trested in escalating dose colrorts of IL-2 (See Sertiosl.Z.Z for dose levels).
IL-? administrntion should commerce l-8 horus after coarpletion of the
perubr:oliaunab infrrsion. IL-? uray be ornitted iu Corrses 2 and 3 ifpatient has
aehieved an uncolfurued or confinned CR, if IL-2 was associated with
siErificant toNicity iu the treating physician's opirrion, or if patient declines
additioual IL-2.
c. Full physical examinatiou is required at screeaiug visit. Directed physical
exarnination is required at all other time poiuts.
d. Currcnt or baseline weight cau tre used {br calculation cf IL-? dose at the
discretiou of the investigator for calculation of IL-3 dose as long as curent
weight does uot differ flom baseline weiglrt by rt0g.a.
e. Labs on Week I do not neetl to be repeated if screening labs were perforured
within 14 days of the starl of keatruent. These labs rray be repe*ted af the
discrefiou of the treating investigator in the week following IL-2 to uonitor aay
abuonnalities that were seeo dwing IL-2 treahent.
f. PTIINR, FTT. rutnalysis (UA). chest x-ray (C)ffi) and electrocardiogparu
GKC) are reqnired at baselire nud on adruissiou for IL-2 (or within 7 days
prior) but ate uot required at every peurbrolizmuab freatrnent visit. These items
can be omitted in patieuts no longer receiving IL-2. CT clrcst may replace CXR
at baseliue.
S. Pregrrancy test is required ouly in uroilleu of childbearing potential (WOCBP).
WOCBP are tho$e who have not been srugically sterilized or have not beer fiee
fromurerses for> I year.
h. Trunor assessment ruoy be performed by iuraging and/or cliuical evaluation.
Additional truror assessurents rnay need to lre petfotmed io confum CR, FR or
PD. See Sectiou 7.i.3 for firll details.
54

Product: Pentbroliztunab
ProtocollAmendment No.:
55
j.
k.
Trunor fissue will be collected at baseline and at Week 13 (* 14 days).
Suburissiou of tissue is strongly e.ncouaged buf optional. Af baseline. fresh
truuor tissue is strongly prefened. but archival tissue uray be submitted instead.
Apprnxiruately lcur3 is requested, or as much as is feasible. Patients are
($courased ts subrnit tissue at Week 13 wlrethsr they ar:e confinuilrg o& study
or dieconfiuuins trcatfllent. See Appendix 11.5 for processing and shipping
details.
The mandatory Safefy Follow-UpVisit shouldb* conducted 90 d*ys (+14 days)
after the last dose of trtal treahnent. or before the initiatiou of a new anti*cancer
treahnent. whichever comes fimt.
Blood collecfiort fbr con'elatives to be drawn pre-dose evsry l2 weelc$ af the
start of each Course (week 1. 13, 35, 37 and theu every 12 weeks). Pre-dose
collection can be drawu at time of other labs. Repeat draw is not required if
schedded treatme$t is delayed for toxicity.

Product: Penrbroliaunab
Protocol/Amentlment No.:
?.0 TRIA.L PNOCEDUNES .A,ND ASSE$SMENTS
7.1 Trinl Procedures
The Trinl Flow Char-t - Section 6.0 surnurarizes the hial procedtu'es to be performed at each
rdsit. Individu*t trial procedrurs nre described in det*il below" It xray be neces*ary to perfonn
these procedu'es at unsc.heduled time poirts if deemed clinically necess{uy by the investigator.
Fruthe.rnrore, *dditioual evaluations/testing may be de€rned necessflry by the Spousor andlor
ltutrerek for reasous related to subject ss&iy. In some ca$esl such cvaltration/testing may be
poteafially sensitivo iu *ature (e"g., HIV, Hepatitis C, etc"), a&d ttrus local regulatione nray
require that addifional iafornred consent be obtained frorn the subject. Iu these cases, such
evaluationdtesting will be perfonued in accordance r,vith those rregrrlations.
7.1.1 Admiristrative Procedurer
7.l.l.t InfornedConsent
The Iuvestigator must obtain documented corsent fiom each poteutiai subject prior to
participating in a cliuical rial.
Consent trust be docmuented by the subjecf's dated sigrrature or by the subject's legally
acceptable representntive's dated siguahne ou * consent form along with tlre dated siguature
of the person co,nducting fte esusent discussion.
For ruinors, *ccording to loeal legislation, one or both parents or a legally acceptable
representative nrust be infonned of the *fudy procedtues attd must srgn the informed eonsent
form approved for flre study prior to cliuical study participatiou. The explicit wish pf n rrriqsl,
who is capable of fonning an opinion *nd assessing this infornration to reflxe participation in,
or ta be withdrawu fiom, the clinical shrdy at any time should be considered lty tbe investigator.
Mirors who are judged to be af an age of rensou nrust also give their writtert assent.
A copy of the signed and dated coo$eet fonn should be given to the rtrbject be$bre particip*tion
in the hial.
The ilitial infon:red couseut fonn, any subsequent revised lvritten infbnned consent fonn and
aily written iufbr:netiou provided to the subject urust receive the IRBIERC's
approvaUfavorable opiniou in advance of use. The subject or hislber legally *cceptoble
represeatative should be infonued in c timely umnner if new infomnfion becomes availnble
that may be rel*vauf to the subject's williugress to cotrtirrue participntion iu the kial. The
conunuricaliou of this hfbrxr*tion witrl be provided and docurnented via a revised conseut
form or addendtun to the original consent form that coptures tlte subject's dated siguahre or
by tbe subject's legally aeceptnble rcpresentative's dated siSnature.
The informed couse*t will contain specific infonnation about the
population, and follorv-tqr reqtriremenls.
56
trial therapy, the trial

Product: Peurbroliaunab
ProtoeoUAmentlment l$s. :
The informed consent will adhere to IRB/ERC rcqrdrelnents" applicable laws and regulations
and Spousor requiremerts.
7.I.1.2 Eligibilify
All irElusiou snd exclusioil erimria will be rerrirx'ed by the invr*tigator: or qualilied designee
to ersure that the subject qualifier for the hial"
7.1.f J *Iedicrl Hixtory
A medical history will bq obtaixed by the investigator: or qualilied desigpee. Medical history
will include all*ctivs couditians, ard any cordition diagnosed withhr tlre prior I0 years tlrat
are con*idered to be *linically siguiticcnt by the Investigator. f,Ietails regarding the disea*e fnr
wh:ich the subject hns eorolled iu thie st*dy will be recorded separately audnot listed as rnedical
history.
Csrdiac and Pulmonnry History
P*tienfs ov*r the *ge of 50 rnust have a cardiac shess test without evideuce of reversible
ischelnia al baseline (witldo 90 days). A cardiac stress te*t should be performed on a patient
reg*rdles$ of age who h*s possible cnrdiac symptoms or is eousidered to be at hig& risk by the
heetiag investigator. Al:y method of stress (exelcise, phanuaeolagic) is acceptable. The test
must inelude imngfug with either ultrasoturd (stress echocardioggaur) or ruclear uredicine
imaging.
Patierts with a his(ory of cluouic lung d.i*eose or healy sruoking should have PFT's perfonned
durius g sgning"
?.1.1.4 Prior rnd Concomitant Medientions Reviex
Prior Medimfions
The iovestigatar or qualified designee rvill review prior medication use, hcludiug any
prntocol-specified washotrt requireurent, and record prior uredicatiou taken by the subject
within 28 days before starting the fial.
Trenknest lbr t&e disease tbr which tlre subject trras enrolled in this study will be recorded
seperately. Any prior use of checkpoiut iuhibitor (e.g. ipilirnturab, pembrolizumab.
nivulumab. PD-LI inhibitor) should lre documented.
Concomitsnt Medications
The investigotor or qualified dasigpee will reeord uredication, if any, takeu by the subject
&.ring the fial All m*dic.ations rel*ted to reportable SAEs ard ECIs should be recorded as
defined in Section 7.2.
57

Product: Pembroliaunab
Protocol/Atnendment No.:
7.I.1.5 Di*e*ss llrtails and Trentmrnts
The iuvectigrtor or qualified de*igrree will obtnin prior aud c rnnnt details regarding dise$se
stahu. The BRAF nrutational status on each subjeet should be documented and recorded as
rnutatedi/600E. nrutated-other. wild type, or nct available. Prior therapies should be
docunerted. Any prior use of clreckpourt iulribitors (e.g. ipiilntunab, perubrolizrunab,
nivolurnab, or PD-LI inhi$i16ss) should be docurueuted.
The iuvestigator or qualified designee will review all prior €a&cer treatmentc iucluding
systemic treatrneuts, radiation and surgeries.
7 .l "l "6 Subsequent Arti-Csncer Therrpy Status
The invettigalor or qualified designee will review all new anti-neoplastic tlrerapy initiated after
the last dose of trial treahnent. If a sub.iect iuitiates a new anti-cancer therapy within 90 days
after the last dose of trial tre*trneat, the Safety Follow-up visit must occlu'before the lirst dose
of the ne,w therapy. Once new auti-cancer therapy has been initiatsd tlre subject will move irto
sundval follow-rry.
7.I.1,7 Arsignment of Suhject Number
The coordinating site will assign each screened patient a subject number.
7.1.I.$ Trid Complinnce (i!{tdicrtion/Confraceptiod0ther}
The investigator or qualilied desipree will review trial compliance regarding medication,
contaception, scheduled sssessmeuts, other.
7.1.7 Clinical Procedurss/Arscssmerts
Atl clinical procetlures/assessnrents will be performed according to the Trial Flosr Chart
(Section 6.0).
?.l.tJ Adveme Event (AE) Mouitoring
The investig*tor or qualified desiEree will assess each sulrject to evaluate forpotential rcw or
worsening AEs as specified iu the Trtal Flow Chart aud more frequently if crur-ically indieated.
Adverse experiences will be ggaded and recorded tlroughout the study and duing the fiollov*-
up period according ta NCI CTCAE Vemiou 4.0 {see Section lI.2). Toxicities will be
characterized in terms regnrding seriousneus. eausality, toxicify pading, and actisn taken rvith
reg*rd to kial heatment.
For srbjects receiving treatment withpernbrolianmab all AEs of rmknolvu etiolory associated
with pembroliztunab exposurc should be evaluated to detemiue if it is possibly an eveot of
clinical iuterest (ECI) of a potentially immunologic etiology (ermed iurmtme-related adverse
events, or irAEs); see the separxte ECI guidance document in Appendix regarding the
identi{i*ation, evaluatisu and mnnageiuent of potenfial irAEs.
58

Product: Feinbroliaunab
ProtocoUAmendmeut No. :
Please re,Ibr to section 7"2 far detailed ittbruretion regarding the assessrttent aud recordiug of
AEs.
?"1.1"2 FuH Physic*l Exnm
The investigiator or qu*lified desigpr*e will perfonn a coruplete physical exarn duriug the
screening period. Clinically sigrrificant abnonual findings should be recorded as medical
lristory. A full physicol exam should be perfonned durfurg screening. A full physical exarn
includes at least these systems: Seneral, HEENT, Neck, Cardiovascular, Respiratory,
Abdomiual, Lymph $odes, Musculoskeletal, Extrenriries. Neurological, Psychiatric, *ud Skh.
When clinically *ppmpriote based on disease location, *ymptours, or cou*orbidities, if nray also
iuclude ophthaknolqqic eye exflrrl, bre*st exsfl1 genitourinary exaru, andor reet*l exam.
7-1.2.3 Directed Physical Exeur
Duriug the treahnent portion of the shrdy. tlre invesfigator or qualified designee will perfonrr a
directed physieal eKalu as clinically indicated prior to trial teafirteut administration.
7.1.1"4 Yital Signr,Il*ight nnd Weight
The investigator or qu*lified desigrree will take vital sigus at screening, prior to the
administratiorr of eaeh dose of trial treatment and af treahne*t diseontinuation as specified iu
the Trial Flow Chart (Sectiou 6.0). Vitnl signs should iuclude terupemhue, pulse, respiratory
rate, weip{rt aud blood pressru'e. Height will be measu'ed at screening only.
7.f.2"5 Eartern Cooperative Oncology Group (ECOG) Performance Scale
Tlre investigator or quali{ied designee will asse$s ECOG sfahrc (see Section 1 1.1} at screenirg,
prtor to the administration of,ench dose of finl treahrert and discontinuation of kial treatmert
as specified in &e Trial Flow Cbart.
7.I.3 Tumor Imagiag snd Assessment of Ditelse
All tumor as$e$smeots will be perfomed nceording to the Trial Flclv Chart (section 6.0). If a
patieut discontinues {reafurent for auy rea$on other th*n progg*ssion, hunor assessnrex}ts will
be doue ev*ry l? weeks (t 14 days) until Week 49.
7.13.f Mrthotls of Tumor Assessment
The prefered iumging modality is CT scan. Other modalities (h{RI, PET-CT, ultrasound,
endoscopy, laparoscopy, cytology. histology) uray be used as adjrurcts. If there is a conrpelling
reasor to do PETICT scans or MRI (e.g. patient lras allerpy to iodinnfed eonfrast), the PI should
be contacted for penuissiou.
All measurements shotrld be taken and recorded in metric aotation using a ruler or calipers-
The saure method of assessnreut *ntl the same technique mtrt be used to characterize eaclt
59
identified and reporled lesion at baselitre and duing follorv-rrp.

Product: Peurbroliauuab
Prototol/Amendrnent No. :
preferred to evalu*tio& by elinicol ex*ruhmtisu rudess the lesio*(s) bei$g followed cannot be
ir:raged but are sssessable by clinicnl exa$r. Combinafions of clinically measurable ald
radiopephically me*sur*ble rre penuissible. For exaruple, the patient uray have dennal lesions
that are urosl accurately measured by ctinical evaluation with a ruler or calipers, aad lynrph
notles that are urost accuraletry rneasured on CT scan"
CytologSr and histology msy be helpfut to di{fsreutiate a complete response from a partial
response.
7.13: RECIST version 1.1
The prirnary set of response criteria for this hial is RECIST v1.1 [a3]. See Appendix 11.3 for
criterin for corxptrete respsuse (CR), partial response {PR), stnble disease (SD), andpropessive
disease (FD).
RECIST vI.l will be *rodified for tkis trial. To accormt for huuor p*eudo-progresuiotl thnt enu
soruetimes occur with irnmunofherapy. it is required that RECIST PD be conlinned os a
strbsequent assessmeff performed 4-5 weeks later (see Section 7.I.3.4 fbr details).
?"1"3.3 Evalu*tion of Best Ovsrall R.erponse (BOR)
The best overall rs$pouse is the best respou$e (T*rget + noo-target lesions) recorded fi"orn the
start of the treahuent until diseese progression/reeuffence or non-protocol thernpy (taking as
referencE for progressive disense the smnllest meastuemenfs recotded since the treatment
started). The patient's best re$pouse assigrrment rvill depend ou the achievement of both
measruement and confinnatiou criteri a.
7.1"3.4 Csdirmntion of PD
Allowing patieuts to eoutirure treatmeut despite ttre initinl radiologic propession takes into
account the obseffation that soure patieuts with melanorna cffI have s hansient hutlor flare in
the fu'st &w uronths atler sfart of ironxmotberapy with subsequent disease resporse.
Jtls mirrirnxl criterin must be met to continue treahneut in patients with rsdiological PD. Such
crtteria may incltrde the following:
l. No cymptorus or sipprs (including worseniug of lsboratory values) indicatiug disease
prngpession
2. No decliue in ECOG perforxrance status or symptouratic elinical deterioration
3. No evidence of rapid progression of disease or of propressive tuuror af critical
aratomical sites (e.g.. cord cornpressiou) requiring urgeut altenrafive medical
interveution
If a patient does uot meet all of the requireruents above, the patient should be rcproved &orn
60
trial immediately for unconfirrned PD rvith clinical deurise. E"

Product: Pentbroliaunab
ProtorollArnenthnent No. :
docruueut tlre odective progxe$siar evsn after discoutiuuafiou of treaturent. Pnfieut* with a
glabal deterioratiou of health status requiriug discontimration of treahueirt witbout objective
evidence of disease propgession at that tirue (not evaluated by confinnatory scan) should be
reported as "slnnptornatic cliuieal deterioration."
For patients who are clioically well and ureet the criteria above, the patient nray reruain on
treatruert at fbe discretion of the investigator, and iruaging should be repeated no less thaa 4
weeks but uo more than 6 weeks later (4-6 weeks).
If the repeat assessment demoffitrates CR, PR- or SD (relative to baseliue) as per R.ECIST vl.l,
treatrnant may be contirued s$ per tr*atment calendar:.
Ifthe repeat assessurent slrows dernonstrates FD (relative to bnseliue or the nadir huror burdeu"
rvhiclrever is surnller) 6s per RECIST v1.1, heahnent will be discoutinued. The development
of conlirmed PD audlor the developnrent of syurptonratie clinical deterioratiou coastitutes
confinned progressive disease. Iu the case of confinued prog6essive disease, sfudy treatrnent
xhould be discontinu*d.
7"135 Canfirmation of PR orCR
The subject's first instance of a PR or CR should be confinned ou a repeat asses$ment no less
thar 4 weeks later (4-6 weeks); bowever, it is accepteble to delay the repeal asses*ment until
the next scheduled intervcl iuragitg study (12 weeks * 7 days) at the discretion of tbe treating
investigator, or if the patieut prefers not to hal"e ao extra CT scnn for this purpose.
A br*psy of any residual lesion may be rned to coufinn s CR at the discretion of the treating
investigators-
7.1.3.6 Determining the date of progression or re$pon$e
For all patients who experience disease proprression on shrdy. the date noted for disease
propessiou is the tilre of the scan wheu it was ortginally detemined, and uot the later dat*
of the coafinnatory scau.
For all patieuts who experience conrplete or partial ou study, the date noted for disease
rcsponse is the tirne of the sca:r wheu it was originally detetmined, and not the lster date of
the confirurotory scan.
?.1.4 Tumor Tissne Collstion *ud Correhtive Studirs Blood Sampling
7.1.{.I Tnrnor Tissue Collection
Tumor tfusue will be cnllected at baselite srd at Week l3 (* l4 daysi. Submission of fissue is
strongly encouragad but optional. At bnseline, &esh tumor tissue is strongly preferred, but
archival tissue may be submitted instead. Approxirnately lcm3 is requested, or as much as is
fessible" Fatieuts are encotuaged to srbmit tissue at Week 13 whetlrer they are continuing on
61
study or discoutiuuitg treatrnenf. The trunor biopsy tissue rvill be

Pr"oduct: Pembroliamab
ProforollAmrndment No.:
iruruunopheuotype of ruyeloid arrd lymphoid cells, PD-LI aud PD-L2 expression by trunor
cells (Qualtek), autigen-specific T-cells. intracelltrlar cytokines and effector molecules, and
lsne exptession *nalysis (N*noString). See Sectiou 11.5 for processiug and *hippiug detrils.
7.1.{"1 Crmdrtiye $tudies tslootl Stmpling
Rose*rch blood saurplex will lw collected at lVeeks l, l3, 25 and 37 and then every 12 weeks. See
Appendix I1.5 for processing nnd shipping details.
7.1,5 Laborrtory Procedures/Assessments
Details regarding specific labarafory procedues/assessrneufs to be perfonned in this trial are
provided below. Laborotory Safety Evaluatious (Heuratology. Chemistry and Urinnlysis)
Laboratory tests ftr hematology, chemistry, urinalysis, and cthers are specified in Table 6.
6?

Product: Pembroliannrab
ProtoroUAmeudmeut No, :
Tnble 7 Lnhorntory Tcsts
63
Hemntology
Chemirtr-v
tlriuul!'sirr
Othsr
Henratocrit
Henroglobirr
Platelet corurt
WBC' (total and differential)
Red Blood Cell Count
Absolute Neutrophil Clount
Absohrte Lluphoclte Count
Alburniu
*ttahne plrosplmtase
.*l*rin. arninotranrferase (ALT)
Aspartate aruinotrarxferase
{Asr}
Lactate <lehydrogeuase (LDH)
Calbon Dioxide *
{CO2 ar bicarbanale)
Uric Acid
Calciun
Chtoride
Glucose
Phosphorus
Potassiunr
Sodiuru
It{apnesitun
Total Bilinrbil
DLect Bilinrblur tI! rotol biltntbin
is ela'sted nbote the upper litrit
af *ornmll
Total protein
Blood Urea Nikogeu
Anrylase
Lipase
Blood
Glucose
Protein
Specific graltty
Microscopic exanr ff
obnonnal
results arc ilolstl)
Udne pregnrancy test t
Sanul p-ltuua* choriouic
gonadotropinf
$-hcc)t
PT (rNR)
aPTT
Total triiodothyronine (Tl)
Free thlr'oxire (T"1)
Thyroid sfiruulatilg horurorre (TSH)
Blood for conelative studier
f Urine or saruor pregruucy te$t orr womffr of clrildbearing potentinl only.
f Ifcon*idered srandard ofcarE in yaru region.

Product: Pembroliaunab
Protocol/Amendment No.:
Labor*tory tests should be perforured try the local laboratory (no centralized labs). Results
mu$t be reviewed by the iuvestigator or qualified desippree a*d forurd to be acceptable prior to
eseh dose of trial heahent-
7*1"6 Withdr*wdlDircontinutfion
Whea a subject discontinue#withdraws prior to trinl coupletion, all applictble activities
scheduled for tlre finel fial visit should be perdor:ned at the tirne of discontinuatiou. Atty
adverse events which are present at the tirne of discontinrrationlwitlrdrawal should be followed
in accordance with the sa{bty requirernents outlined in Section 7.2 ' Assessing and Recording
Adverse Events. If the subjeet is willing to ndhere to {bllorv-r1p procedures, all assessments
listed in &e Safefy Follow-up and Long-tenu Follow-up columns in fke Trial Flow Chart in
Sectioa 6.0 shouldbe compleled axdrecordeduntil withdrawX of couseut or de*tk, so thnt dat*
can be annlyzed in accordance with the intent to treat prtnciple.
1.1.1 YisitRequirements
Visit requiremeufs are outliued iu Section 6.0 - Trial Flow Chart. Speeific procedure-relhted
details are provided above iu Section 7.1 - Trial Frocedures.
7.I.7.f Sereening
Strbjects will be smeened for eligibility. The fucltrsion aud excltrsion criteria will be reviewed
at the Screeniug tisit{s). Eligible zubjects will be eurolled before heahnent start nfter
verification of fulfilling all inclusiou criteri* without matching any exclusion criteriou. All
requirements rnust be completed ns nrsre than 4 weeks prior to start of treahrent.
7.1.7"2 Tre*tmert Periotl
The treafuent period is di'rided into 4 courses. Each course consists of 12 weeks. Courses l-3
uray include IL2 therapy. for a nraxinuun of tluee cowses of IL-2 per patient depentling on
tolemnce and respouse. Course 4 consists of pembroliznmab rnonotherapy for all subjects.
On-Treatmtnt $nfefy Asrersments/Treatment risits
Safety will be evaluated fcr all heated patients ueing the I'{afianal Caucer Institute (NCI)
Commo* Terurinolopy Criteria for Adverse Evenfs (CTCAE), Version 4.0
(http://ctep.cancer.govlreportindcte.ht'url). SaIbty assessulents will be bassd on medical
review of sdverse event reports and the results of r.ital rigu meastuemeuts, physical
exaurinations. and clinical latroratory tests. Subjects who arc est willing to adhere to the study
calendar should be reuroved fi:om active keaturent nud enter survival fnllow-rrp mode.
?"1.?-3 Post-Trestm*nt Yisits
If a patient does not receive aay assipured protocol heatmest, follow-up data will not be
collected. Holvever, flre reason for not starling protoeol trealilreut must be docuuented on the
offheahuent fonu.
64

Product: Fembroliaunab
Profocol/Alnendment l{s.:
Slfety Follow-Up
The nrandntory Safety Follow-Up Visit should be couducted 90 *14 days after &e last dose of
trial heatment or before the initiation of a new auti-cancer treatme[t, whiehever comes first.
All AEs that occru in tlre 90 days followiug last study treshne$t (but befbre the initiation of a
new anti-cancer beahn*ut) should be recorded" Sulr"iects with an AE of Grade > I rvill be
followed uutil tbe resolution of ihe AE to Grnde 0-1 or uatil the begilnii$g of a new auti-
neoplastic therapy, whichever occurs {irst.
Sulr.iects rarho are taken offtreatmelrt for reasons other thnn progressive disease uray remaiu ou
study aud complete study requiremeuts wrtil the end of the 2 year study period. Srrbjects should
complete ou-study hunor assessruenfs at fhe scheduled tinrepoints despite discontinuing
therapy rurtil they initiate new anti-caucer treatrnent or witbdraw their consent.
The end of on-*trdy pembrolizumab treahent is defiued as 2 cale*dar year$ &om the date of
errolhnert. Following the end of the shrdy, tbe investigator may cltoose to contiuue
pembroliauuab off-study in stablelresponding patients at hislher discretiot.
Loug-trrm Follow-up
7, L. 7. 3. 1. 1" 5'u &sequ rrn f .$ n f.f -Chrrrer I'ft erap4y .$ln tus
For subjects who discoutimre trial bestulent for areason other tlran disease progression. every
effort should be made ts colleet information regmding disease status uutil the start of uew anti-
aeoplastic therapy. disease propessiou, death. At the end of the treahneut period, the
investigator m*y choose to continue perubroliaunab off-shrdy at hislher discretion.
Iufonnatiorr regardiug post-study anfi-ueoplastic trealmeut rvill be collected if new treatment
is initiated. In-person visits are not required. Once new anti-catrcer therapy has beeu initiated
the subject will be followed for survival ouly.
7. 1.7.3 " 1. ? Survf unl ftlfior.v-up
All subjects will be fullowed for suvival. The study fearn should nrake contact with the sulrject
every t2 weeks (starting sfter the EoTlSafety follow-up visit) to asses$ for survival status tmtil
death. withdrurval of consent, or the eud of the study, rvhichever occtus first. Telephone visits
ard electronic corumunications are pennissible if in-persou visit are incoovenient. hrdilect
c.otrtsct tluoug$ another medical provider (e.g. a local nredical oncologisl's o{fice, farnily
plrysiciau's office, or lrospice) is acceptable. This should be docruneuted with dated
dscuuentation {such as l*bnrafory results or an affice uote) or a research note created by the
study teenr. The date of death xhould lre recorded. The on-line Socinl Seeurity Dea& Index
may be used to verify the date of death.
7.2 A*resring rnd Recording Adverse Evenis
Au ndverse event is rtefined as any untorvard medical occulrence in a p*tieut or clinical
investigatioa strbject admiuistered a phamraceutical prnduct and which does not necessarily
have to hsve a causal relationship with this treakuent. An adverse event can therefbre be any
65
uilhvorable and wdutended siEr (including an abnonnal

Product: Pentbroliaunatr
Protocol/Atnendmeut No.:
synrptom, or disea*e temporally associated with the use of a nredicinal product or protocol-
specifred procedure, rrhettrer or not cousidered related to the medichal product or protocol-
npecified proce&xe. Any worsening (i.e., any cliaically sigpiflcant adverse chauge in
frequency aud/or intensity) of a preexisting condition that is teurporally associated with the use
of the strdy drugs is also fit adyer$e evsrt.
Changes resulting from nonual growth aud developurent that do not vary significantly in
freqtrency or severity from expected levels are uot to be considemd adverse event*. Exar:rples
of this may inclnde" but are not limited to" teethiag, fypical crying in infants and children and
onset of menses of menopfluse oecurring at a physiologically *pprupriate time"
druS(s) includes any phanuaceutical product, biological prodtrct. device. diagprostic
or protocol-specified procedrne, whether investigatior:al (including placebo or acfiYs
Adverxe evenfs rusy occlu &rring the course of the use of The study de'ug{s) in clinical trials
or within the fotlow-up period speeified by the protocol, or prescribed iu clinical pr*ctice, &om
overdose (wlreth*r accidcutnl or intentiond), from *b$se and from withdrawal.
Adverse events may also sccur in screened subjecfs drring arry pre-allocafion baseliue period
as a result of a protocol-specified inlervention, including washout or discontiuuatiou of usual
therapy, diet, plaeebo treatment ar a procedure.
Propession of th* career uuder study is uot csusidered an *dverse evenf tmless it is coneidered
to be dnrg related by the iuve*tigator.
All ndverse event$ will be recorded from the time tlre conseat fonn is sipred tluough 90 days
following cessation of treahnent, or until the initiation of srtbsequent therapy. whichever comes
first. Th, reporting timeframe for adverse events nreeting any serious criteria is described iu
se(.tion 7.2.
All adverse sveuts of ggade 2-5 rnust be recorded in &e eC&F in OnCore. Adversa events of
grnde I ueed uot be iaphued iu the databnse unless the grade I AE i$ detenuined to be
iotolerable and/or leads to a change in dose or schedule, or the treating investigntor wishes it
to be reported in fhe database.
7,2.1 Immsdirte Reporting of Adverse Events
7.2"1"1 Serious Adverse Everts
A serious adverse event (SAE) is any adver*e event occlnrlng at auy dose or druhry any use of
thr study drugds) thaf:
e Results iu death;
r Is life threotening;
66
Shrdy
agent
coultli
rrv!
Results in persisteut or sipprifi caut disabilifylincapacity;

Product: Peurbrolizruuab
PmfocoVAmffidrnetrt No,:
r Results in orprolalrgs an existing iupatient lrospitalization;
r Is a cougenital anomalylbirth defectl
e Is a oelry ca$eer (that is not a condition of the sttdy):
r Is associated with an overdose;
r Is e$CIthrrfunportanf ruedical weut
* Ctxnmou nud expected toxicities related to IL-3 arlminishalion will rot be considered
report*ble SAEs.
7.2.t.2 SAE Reporting tof
Any SAE. or follow-up to a SAE, iucluding death due to any cause other than pl'ogrression of
the cancer ruder shrrdy thht occtus to any subject fiurn the tiure fhe corsenf is sigued througlr
90 days following cessatiou of treotment, or the initiation of new anti-caucer therapy,
whichever is earlier, whettrer or uot related to the shrd
s), nrust be
withirr 24
horus to Sponsor-Investi
67
Additionally, any sedous adverxe event, considered by an iuvestigator who is a qualified
plrysician to be related to the study dnrg(s) fhat is brought to the attention of the investigator
at any tiure outside of the tirue period specifiecl in the previolls p*ragraph also must be reported
,r.rrrlurflrErlI
n are to be forwartlert to ttreJ
up for outcome.
7"2.1.3 SAE Reportirg to Prometheus

Produrt: Penrbroliaunab
ProfocoUAmendrnent ro. :
Common *nd expected toxicifies related ta IL-2 admiuistratiou will nof be co,sidered
reportoble SAE$. For guidance otr corlltrror aud uueornmoa tpxieities "*p*1ga with IL2,
investigators may re{brto reo€ut-Il--2 guidelirys [3aJ. During IL-l adrnini*t utiou" only SAEs
of Specinl luterest will be cousidcrcd repo*able. 
-
IL-2 Related sAEs of $pecial Interest ulusf be reparted lvitbin 24 horrc of tbe investigntor's
knowledge of the eveut"
Ao IL-2 Relat'ed SAE of Special Intmest is *n SAE tlmt occtus dr*iog IL-Z reahnent or within
14 days after IL-? hestment, aud ir defined by ury af thE fouowing:
I Atrygrade3 orgreatsrioxicifythatdoesnotirnprovetoEgeds l orbetterwithin l week
' 
Exceptions: gr*de 3 arthralgi#myalgias, grade f fatigpre, *nd pgnde 3 aurylnse
or lipase elevafion, which should all be considered uJn-seriouJAEs.
o Any reporlable ECI (See Apperdix I1.4 arrd full length ECI Guidalce Document)
' 
Exceptiot: Bgade 3 skiu AE thsf improves to grade I or better within I week.
r llypoteusiou with systolic,BP<80 and not responsive to tluid resu$citation andlor
vasopre$$0r$
c Fuhuouary*demarequiriug infubation
r Pnerunonitis (Grade 3 or 4)
e Renal dysfirnction requiring dialysis
o Gr*d* 4 cardiac dysrhytlrnria or Grade 2 or 3 dysrhyflunia not easily colholled with
medical menagemeut
r Myocardial isclremin {Grade 3 or 4} *r infarction or synrptomatic myoc*rditis
r Frricardia! tarnpouade
e Bowel ischemia orperforrfion
r Life tlueoteniug sepsis
r Severc altered menfal st*tus or coma
' AIty other severe or lif,e-tlueatedng toxicily which, in the opinion of the heatilg
investigator, woutrd preclude fiuther treabneni with lt-2.
$nf ene1tqeeb nuyofthecriteria above shotrldbereportedas auIL-2 RelatedSAE of Special
Ilttsest to the IRB, h{erc.k, and Prometheus using the above SAE reporting procedtres.
68
7.2.f.5 Events of Clinical Interest

Productr Pernbroliaunab
ProtocoUAmendment No.:
Study dmg{s}, as defioed in Section 7.?.4 - Definition of an Overdose for
Reporting of Overdose to the Sponsor. fhat is uot associated with clinical
sJilnptonrs or abnormal laboratory results"
3. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of
normal and aa elevated total bilinrbin lab value that is greater thnn or equal to 2X the upper
lirnil sf 66tual and, at the sarne tiune, arr alkaline phosphatase lab value that is less thao ?X the
qpper limit of ncrnrel, as d*emnined by way of protocol-rpecified l*boratoly testing nr
unscheduled lobor*tory testing"*
*Note: These criteria are based upon available regulatoly guidauee dac:umeuts. The
pu{po$e of lhe criteria is to specify a threshold of abnonral hepatie.tests that may require
an *dditional evslrration Ibr an underlyiug etiology. The hial site gpridance for assessmert
aod fnllow up of these criferia car be found in the Investigator Trial File Binder (or
equivaleo$.
1. Additional adverse errents:
A separate puidance docunre*t has be.eu provided entitled '"Eveilt of Clinical lnteresf
Guidance Doctuneut"- This docrunent can be fomcl in Appeudix ald provides gnridauce
regarding ideutificatiou, evaluatiou and nranngeurent of ECIs arrd irAEs.
ECIs futh uo$-serious and seriou$ adverse eventv) identilied in this guidance document
from the dste of Srst dosc throug& 90 days followiug cessation of freatmeut, or 90 days
after the initiatiou of a new alticancer
whichever is earlier. need fo lre
NOTE: Hypophysitis
Hypophysitis is defrned as presumed fuflanrnatiou of ihe pihritary glaud based on clinical,
lnboratory and irmging d*tn. Fcr this protocol, hyllophysitis should be recorded as an AE as
"Endrocrine disorders-Other (hypophysitis)" if 2 ortnotn of the fiollowing CTCAE tennr co-
occurring in the sarne subject: adrenal insuffrcieucy" hypothyruidisrn, and hypagouadism.
69

Prcdurt: Penrlircrliaunab
ProtoroVAmendrnent No, :
Nolr-serisu$ Events of Cliuical Interest will be fonrmded to Merck Global Safety and witl be
handlediu flre sarne s]flaneras SAEs-
1.2.2 Recortling AEs During Inpatient llospitalizafion for Study Therapy
Events of the inpatieirt cetrse should be do'eunrented, including detoiled infonnation abouf
AEs.
The sfudy tearn *u, ehsose to sruuurnrtze the infornration in the Discharge Srurunnry or in a
ResearchNote using the followiug tenrplate:
Summsrv of Resesrch Data from Innstient Ilosnitalization
r What was duration of hospital stay (fur days)?
r How rna$y doses of It-? did the patient r:eceive? _
r Did the patient require any of tlre Ibllorving dwiug this *dmission?
a. Trausfer to a higrher level of eare? YesNo
7A
b. Vasoprcssor therapy?
c. Supplemeataloxygen?
d. Ventilator?
Yes/![o
Yes/l.{o
Yes,rNo
r List all AE's during the hospitalization wifh highest grade, start and stop daies, and
atkibution.
AE
Grsde
$tart Date
Stop Dafe
Attribution
I
7..
3.
4.
5.
6.
7"
8.
9.
I0.
1.2-3 Sv*luttirg Adversc [vrnts
An investigator who is a qunlifred ptrrysician will evaluate all adverse events according to the
NCI Comnrou Tenninology for Adverse Eveuts (CTCAE). version 4.0. A*y adverse event
which changes CTCAE grade over the course of a giveu episode will have each change of
grade recorded ou the adverse event csse report fonuslworksheets.
All adverse eve,nts regardless of CTCAE grade must also be evaluated for seriousness.

Pruduct Pembrsliargsb
PruimoUAmmdment lyo":
Trble I Evdunting Advorrr Eventr
Au iuwstig*tor w&n ic a qrulified physiera& will eval$ete all *dverse evenk as to:
7t
1.{.0 cTcAf,
llild; $lmptourdc or mid rf upt"mi;
trIo<lemte; minhnnl, locrt or oonixt asil,e infrrvetrficu
Sel.rre o'nredically signtnrlnt Uut uoi
indic*ted; disabling; thniting srlf-carc tIlL.
De.th rel{tFd to,q.E
Serioulne;r
Rcrults ln drrth; or
ttrtrY*t*{"
+gt inqlude an [dversl *lent that. had it occrmed io a uore srver fqlgr. migbt have causrd d*a&.): or
iol of ure'* abi[ty to condtct nmnrslm6ilGG
fRerults in or p
if &e hospihhzati,on is a precautiooury **"o* dcontinued-okervahon. Qrlote: Hospitalzatrou [ncluding hospitrlizariolr for ra eleclive
a*, *t ""*tlt"i. " r"ir,f, adverse eveut,); or
b defect (rn offspnug of rub,ecl tokns the
Is I aerr clncer;
rs xol a coodttroa ofdre
:ff;;ilffi;;-;il
Olhsr hrportrtrt
tlreateuiug. or not re4rire hosgntxlizrdif,@G
yve*edeot{en.*J**;*';ffiffiJilfi ffi',e#i;ffiffiffi ffi ffi f'ffi friT,f--ffi f ffi l,frff*o*
lo prevenl one of &e outcornes tisted pr€s.iourly (desi$st{d above by a t).
fflot'*u** *nro*i
Rel*tionrhip
io trst dt'ug
Did the Shdy dnrg(*) "r* th*
**,f*g:: *f,Huf*rly3l-:::1{1y'1 
',god/d,tJ *r,,ru 
"o *" q;"* ;;;;tor *orrrshe* tbal suppc,rts the
cmsality uoted or lteAE form,enmrei thala mdically q;[fi.d ai*""*t of raasatirywas dme. This uidrled docffiffiriffir|iffi rr,,t
required regtrletory time &aIIe. Thp critena below are intended as refereoce gurdehnJs to asrist the iryestigator in assesstng &e likelihood of *
relatioanhip between &e test dnrg and the sdverse eveut based upon the avaitlUte informatioo
Tbt foltorring rorllponetrls {rf to he used to sss.tt the relatlorship brhrern thr stud}' drug(s} f,trd th. AE; the gnea*r he corrrlahm *rth the
Ws 
(ro e$mber end'or istelrsity), tle rllore tiiely tle sttr{' *1gts) crusei tm ilver:e eveat (AE):
to lte Strdy dnrg{s) srrch as: reliable hisCIry,
Did the AE follow rl a reasonable t"*1rool
I, the tinre of o[set of tLe AE cornpatrbh rvith a drug-urdrwed effecl (applies to brals ivith overt
Is ttre AE oot reasotat ty.*pti
eolrronnrental factors
Reletlrnship
to Study
drug(r)
{continu*d)
trrr to be us(d to *ssrrs tho relrtionship b€f$'e!q tte test orug io- ttt er: lconulueo
Wasj$ stug qntS(c) Cs"anrlnuea or Oosetixpo*relfuqr@ECiitT
If ym, did lhe AE resolve or impove?
* {y*, this rs e poaitive dechallergt. If no" &ir is a uegrtive dec&alleoge-
flf,-.a:,:-:]-:::P }rl*lt- lf: (lr&e AE fsslllted rn &nth or perrnaa&r or.ua;tp g; tbe AE resotYedrimpnrved
desprte cmturuanon of ttre siuay aruets);'or (3) the bial is a smgk;orJ&ug ;lati; ; (g'drffid*g(rx;t *1ili ** *-

Prcdurt: Peiubroliaunab
ProtocoVAmendment i\b. :
72
Rechallenge
Wrs the stbj*ct re+xposed to tlm Study dnrg(s) m 6rs chdy?
Ifyer" did &e AE recrr or worsel?
If yes" &r is n pcitite rechallerge" If no, this is a uegative recb*lleage.
(Hote: Tbis mledon is rct applictble il (l) &e mitial AE resulled in death or permanenl dirabi[ty, or (I) ltre hial is a shgle-
dore &ug trial); or (3) Study drtg{s) ir/rre usod only one tine).
NOTE; IF A REC}IALLENGE IS PI"ANNED TOR AN AI}VERSE EVSNT WHICH WAS SERIOUS AND WTIICH MAY
ITA\IE BEEN CAU$m BY THE ETUDY DRUff(0), Ofi.IF REEXpOSUEE TO TIIE SI"UDY DRUO{$) POSE$
ADDITIONAL POTE}TNAI $ISNITICANT RISK TOTIIE SUBJECT, T}IEN TI{EREC$A"LUENGE MUSTBE
APPN.OYS.D IN ADVANCE BY THE U,S. CLI}fiCAL MONITDR AS PER DOSE MODIFICATION oUIDELINES TN THE
pRoTocol".
rs Se clinical/pttlologicnl pmseatrtioo of tle AE cuoxisteut wi& pevious knowledgr rrprdiag es Sltdy dug(s) or &uS clrss
$*ommlogy or toxicologf
The a$s€s$rrcnl of elationslup wrll be reported on the case reporl fornrs lwortsheetl by ur ini.e*t gator wh
judgmeot, inctudlag consideratioa ofthe above elemealr.
Remr^d ont of the lollowing
U3r thn follnxing s{alt of crlf.rir r guidaner &ot rII rritcrra ensl be prc$cot to bl indiettivr of a Study drug(t)
r*trfionrhg)"
Yes, lherr is r renmnrble
posrlbiutl' of Stu$ drug{r}
rcl*tionslip"
There is eddeoce of exporurt to ee Study drug(*, I}s temporal seqtwce of the AE orxe{ mlative to Ae a&uinrstratioo ofere
Study dmg{s} is re.{sonsble. Tllr,e AE is morr likely erplained by the Study drug{s) tlua by another cture
lto, therr i* not, rf;rsoorbb
$oisibili$, Study drug(s)
relntlonship
Subjed did not receive tle Study drug(s) OR tenrporal sequence of dre AE orse{ rdative to a*ninic*ation oftnC Shxry arug(s) ls
uot reasonable OR tbem is amtier obvious cause of the llE- (Also cut*red for a subject witb overdosr rri$out rn asroriat*d AE")

Product: Penrbroliaunab
ProtocoVArneudment No. :
'/3
7'2'1 Delinition of an overtlose for This Protocol and Reporting of Oyer6ose to
r
-I-!ial, 
ay o'erdose of peurbralizurnab will be defi,ed as aay dose of 1,000
nlg or greater (:5 tirues the indicated dose). No specific infonnatiol is available on the
treahnent of overdose of pernbroliaunab. Appropriate supportive treat$rcut shogld be provided
ifclinically i[dicated. In the event of overdose, trr" 
"rulu.islrould 
be observed closely for sipr]s
of toxicity" Appropriate supportive treahnenr should u" pro";o*ali;[*;-uylrJi*r"a.
If an adnerse event(s) is associ*ted.*tl ('tesults ftoru') the overdose of a Study dlrg(s), the
adverse event(s) is reported as a serious adverse event" even ifno other seriousness criteria are
rnet.
ffi rff t'1.l;:ffi*,fiffi n:?:,f rtxi,T-i::x,lx[:*nfi '}:::,Hr
sedous Eveut of Clinicnl ktterest (ECI)" using tlie tenninology "accidentai or jnteutional
ol.erdose without adveme effecf .,'
1.2.5 Reporting of Pregntncy and Lactstinn trl
Altlrough pregnarcy and lactatiou are not corsidered adyerse eveuts, it is the responsibility of
i[vestigators or tlreir designee$ to report any pregrnncy or lactation iri a subject (sporrtaneously
r-eforte! to thern), **{*U the prepsraucy of a ruale subject's fealale paruei thai occurs dtging
the trial or rvithin I20 days of completing the trial cornpleriug the trial. or OO Aays followi,!
cessatiou of treatmeut if the subject iuitiates new atticaucer therapy, whicher.er is earlier. All
subjects and fernale partners of male subjects who become pregmant mrut be followed to the
completimrltennination o.f the pre$la$cy. h'eBnaucy outcoures of spontaueous abortion,
nrissed abortion, benign hydatidifbnn rnole, bligfited ovum, fetal deati, iutragterjne death.
uriscaria$e arrd stillbirfi must be reported ** ,*itoru eveuts (Inrportanf Medieal Events). If
the pregrancy continues to tenn, the outcome (health of iufant) mirst also be reporled.
7.2.6 sponsor Respcnsibility for Reporting.&dverse Evsntr
All Adverse Events wilt be reported to regulatory nuthorities, IRB{ECg agd investigators in
aceordance with all applicable pdobal laws and regnrlations.

Product: Pembrolizumab
ProtocoUAmendment No.:
74
8.0 STATISTICAL ANALYSIS PLAN
E.1 Summary
Subjects with advanced melanoma will be treated with pembrolizumab (200 mg IV e
3 weeks) beginning at Week I and escalating doses of lL-2lo,ooo, 60,000, or 600,000IU/kg)
beginning at Week 4. In the Phase Ib dose-iscalation portion of the study, u..ruul will start
with the lowest dose of rL-z (6,000 IU/kg IV Q8 hours) *iir, u cohoft size of 3 subjects. If
DLT is reached in.0.out of 3 subjects, sequential d.ose escalation will proceed to the
intermediate and high doses (60,000 and 6o0,0b0 IU&g, respectivery), also ,ring u minimum
cohort size of 3 subjects." Based on the data from ttre-ptrase tb dose-escalatioriportion, the
maximum tolerated dose (MTD) will be determined. Ifno MTD is reached, 600,000 IU/kg will
be considered the MTD' The Phase II will be a two-stuj. A"rign, Hl:31oh, H;:l7yo, two-
stage design for futility analysis. The primary endpoint-is the best objective response rate
(BoRR).
8.2 Phase Ib Escalation procedure
The study will use a Semi-Bayesian modified toxicity probability interval (mTpl) method for
Phase I dose escalation portion[44]. The starting cotrori size will be 3 patients, buithe method
can handle varying cohort size when real data have different cohort sizes.
Subjects will be enrolled to the Phase Ib portion of the trial starting with Cohort I (Table).
Subjects will be followed for 6 weeks to monitor for dose-limiting to-xicity (DLT).
The following table displays the escalation/de-escalation/stay/ decisions using the set-up:
maximum number of patients at a given dose:18, true probability of to*i.ity ptio.:, and the
higher and lower ends of the equivalence interval :0.05.
The required sample size is 9 - l8 subjects. There will be no within-patient dose escalation.
Number of patients treated at current dose
1
2
3
4
5
6
7
I
9
10
11
12
13
14
15
16
17
18
g,
tr
Li
or)
gt
El
o.!
-io'l
4tlEi
=lzl
0
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
1
D
S
S
S
S
E
E
E
E
E
E
E
E
E
E
E
E
E
2
DU
D
S
S
S
s
S
S
S
E
E
E
E
E
E
E
E
3
DU
DU
D
S
S
S
S
S
S
S
S
S
S
E
E
E
4
DU
DU
DU
D
D
S
S
s
S
S
S
S
S
S
s
5
DU
DU
DU
DU
DU
D
S
S
S
s
s
S
S
S
6
DU
DU
DU
DU
DU
DU
D
S
S
S
S
S
S
7
DU
DU
DU
DU
DU
DU
DU
D
S
S
S
S
8
DU
DU
DU
DU
DU
DU
DU
DU
DU
D
S
9
DU
DU
DU
DU
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
DU
DU
DU
DU

Product: Peurbroliaunab
Prolccol/Arnrndmetrt liio. :
8.3 Phrse fI Two-Stsge Derign
Tbe phase II rvill be a fwo-stege Simon's lninhusJr desiptn with up to n:48 patieufs to test
H0:17% versus Hl:3OYo at alpha:0.10 and power=0.S0with an iuferiu frrtility aualysis wher
1l]3 PStienjs response dflt* are available. If 3 or fewer re$pouse$ are obsened during stage
l, then the fiaI is stopped early. When the trial coutinues to completiou of all 48 patiiuts,lf
12 or more resporses are observed, rve then reject H0:l7or6. We will also estiurate ttrre BORR
rvith a 950.6 coufidence i*telval, which will be corupared to the well-docuurented IL-2 RR of
16-17% to justi$ or fbrgo a raudomized trixl cornpariug the cornbiuation to IL-2 aloue.
8.{ Delinitionr of T*rmr
8.4.1 Defrnition of evalunble for response
A subject is ev*luabl* forrespouse if helshe received at least I dose af*-2and at least I dose
of pembrolinunab, *nd completed at least I oa-shx$r resport$e assessment.
8.{.2 DeXiniticn of eynlus}le f*r toxlaity
A subjecf is evaluable for toxicity if he/she reeeived at leasl I dose of IL-? and *t least I dose
of perubrolianuab.
8.{.3 Drlinition of DLT
Dose limiting toxicity (DLn is defin*d by the &llowing critsria:
75
17
OU
ou
OU
DU
OU
DU
DU
13
BU
SU
BU
DU
0u
DU
14
BU
DU
DU
DU
OU
15
DU
DU
DU
DU
{6
ou
OU
OU
17
DU
DU
{8
otJ
E = Escalate to the next higher dose
S = Stay at the cunent dose
$ = De-escalate to the next lower dose
U . The cunent dase is unacceptably toxic
MTD = 30Yo
Epsilonl :0,05
Eprilon?:0.05

Product: Peutbrolinunab
ProtocoUAmendrnent No. :
Any Grade 4 or 5 toxicity that is possibly, probably, or definitely aftributable to the study
ageut or ageirts *ndocctrs druing the first 6 weeks fi"um tbe initiatiou of study keahnent
constitutes a DLT.
EXCEPTIONS: Tlre following Gr*de 4 toxicities are expected with high-dose IL-2
teahnent and fend to reverse with holdiug IL-2 heaturent and providing supportive care
mea$ure$, including intubafion, vasopre$sors and anticoagulants" The following Grade 4
exceptions do not constihrte a DLT:
r Venous *cce$$ complicstion. Crrade 4 is definetl as Enrbolic event including
pulmonary Embolism or life-tlueateuirg thrsmbus.
r HSrpoten*ion. 6sade 4 ix defined as Life-threatenimg nnd urgelrt intervention
indicated.
r Urine output decreased. Grade 4 is defined as Anuria (<240 rnl in 24lu)
r Pulrnonu} edeura. Grade 4 is defined as tife-tlreateuing respiratory compronrise;
urgent interveution or intubatiou wiflr ventilatory support indicated" Puhnonary
edema re,$riring furtubation fior < 72 horu's is acceptable.
r Cytokiue rcle*se syndrome" Grade 4 is defined as Life-threatening consequooc€s
requiring prc$sor or veutilatory supporf.
Any Grade 3 toxicity constitutes a DtT if it meets all of the following pararueters:
l. toxicity is possibly, probably, or definitely attributable to the study agent or agents,
and
2" toxicity occurs during the first 6 weeks from the furitiatiou of study treatmeut, and
3. toxicity does not resolve to gpnde 2 or less within 14 days of onset.
In addition io the nbove criterin, DLT is also defiued by any of the following heaturent-
emergent coahaindic*tions to IL-2:
r Sustained venkicular tachycardia (>5 beats)
r Cardiac arrhythmies not conf,olled or unresponsive to mnnagement
r Chest pain with ECG ckauges, consisteot with onginn or myocardial infarction
r Cardiac tamponade
r Intubation for >72 hours
r Rend failure reqrriring dialysis >7? hours
o Coma or toxic psyclrosis lasfing >48 hotus
r Repetitive or dif{icult to conh'ol seiaues
r Bowel ischernia/perforatisn
r GI bleeding requiring sur$ery
e Life-thrc*te$fuIg hyperseusitivity to IL-? or my component of &e Proleukin
fonuulation.
A pade 3 laboratory *bnormalify without clinical symptomatology does not define a DLT.
Speeifi c examples iuclude:
76

Product: Penrbroliaunab
Profocol/Amendmeut l$s.:
77
r amylace elwation withouf epigosric pain and vo*riting
' hPerbilinrbinemia aad ncnsetriuitis without abdourirral pein or teuderuess
I 
^elech'ol)'te abnon,alities, incrudi,g - aeidosis, hyporuaguressrnip, hypocarcemia,
lryt1rda, hypophosphatemia ood hyprurt **iu *irrr*rt .onpt rri*J or mrxcl*
weaxness
r hematolagr* abnonnalities, includiag lyryphopenia neutropraia, anemia and
tbrombocyropenia
P:lare exarnples of expected laboratory ab[ouusliiies that occlu during treahent with
high-dose IL-2 which are enpected to reJolve with n"rai"g n-2 heatruenrt ald providing
supportive care.
Y"t1'h* lulf of patients e4perience tr*nsieut grade 3 toxicities during lreahneut with higft-
dose IL-2, which juatifies *is skict de&rition of s DLT.
8.4.4 Delirition of DLT observstion period
subjec'ts will be uronitored for dose-limiting toxicity OLn for tlie first 6 weeks after the
iuitiation of shrdy Seainrert. AEs that oceur ater thsitfuire rvill not be considered DLTs.
8.5 Jurtilic*tior of Stmple tize
The sample size is 60 evaluable subjects. We anticipate enrolling 6z-6s patients iu order to
obtain 60 evaluable patieats.
Approxirnately 9-18 patieuts will be treated in the Phase Ib portion of the rial.
1$1o}3*ly 48?ntients Yil!* require{ for the Phase II, rwo-stage dseip with Hl=30%,
}IFIT96" $r futitity analysis. Phase 
-Ib 
subj*cts ke*ed *t ihe MTD will be included in lhe
ir.o-stage fr*ility analyxis; theee subjects will be i*cluded in the detenuination of the phaxe II
prirmry endpoint.
8.6 Amlysis of Primwy 0bjrctiver
8.6.1 Intcut to Treot Aunlysir
If the subject is rvilling to adhete to follow-rrp procedrues, all assessments listed in the Safety
Follow-up and Loug-term Follorv-up colunrrs in the Trial Flow Chart in Section 6.0 should be
conrpleted and recorded until witbdrarval of consert or deatll so fhat data can be analyzed iu
accordauee with the iutert to treat principle.

Product: Peutbroliauuab
ProtocollAmeutlmrnt No. :
8.6.1 Phare Ib
The primary endpCIitrt of the Phase trb will lrc the toxicifyltr{TD" If no MTD is resched, ilre
600,000lUlkg dose will be called the MTD. Tlre coordinating eenfer will communieate the
detemrinatiou of the MTD via an electroaic rlterno to all participating sites. At that tirue, the
Phase Il portion urill open to accnral.
8.6.3 Phase II
Thr Prirnary Objective is to characterize the eflic*cy of the IL-2 itr combination with
pembrolizumab using the prirnary endpoint of BORR as per RECIST vl.l. BORR rvill be
calculated in the overall shrdy population and in subpopulations that have eird have not
received prior therapy with checkpoint inhibitor.
There will be a subset analysis of RR in lrurg vs. urelauorna subjects, as rvell a PD.l rarve v$.
PD-l re&actory. PD-l re&actory is defined as baving received prior freatneut with PD-I/PD-
Ll contsinin$antibodies in &e ndjuvantormeta*tafic setting S/e estiurate 7596of the potential
subjects rrrill have received keahrent with a checkpoint inhibitor prior to shrdy entry. The
BORR will be aralyzed by prior treatrnent status.
8.6.3-I Definition of Positive Primary Entlpoint
We assume that objective response rate for high dose IL-2 alone is no greater than l6-l7a/o.
Therefore if the effeet of adding pembrolizumab to high-dose IL-2 were 30ori or better, this
would be a clinically meaningfirl keatment option in this population, which is expeeted to be
larg_ely (75o/6) pernlxolinunab re&actory.
It is nst knsrvu if the efficacy of IL-3 is affected by prior ilrulune checlpoint blockade. but
based on the available data the rcspsn$e rate is expected to be similar. In a prospectively
collected registry shrdy of ruelanonra and renal eell carcinoma pafients wlro received PD-l
inhibitor or ipilimru*atl prior to treatmeut with HD It-2, the RR to HD IL-2 was I 7"7?"o or 915l
patients [45J. h n sirnil*r but smaller study of paiients wlm received PD-l fuhibitor prinr to
beaftnent with tID IL-2, the respotrse rate was 8.3% or l/1? patients [46]. In general, iu-elass
cross-resistarce with inunuaotherapy agents is not observed, and therefore, this justifies the
inclusion of both checkpoint-ualve aud checftpoirrt-refraetory p*tieuts in this protocol.
The olrjective respo$$e rate for pembroliaunab re&actory population is dif{icnlt to estimate
because the etTectiveress of rechallenging with pambrolizuurab is unknown. For pruposes of
&is study it will be estirnated to be l0Yo in tlre truly refiractory population. Patients who lmve
received prior heahnent with PD-l inbibitors and derived clinical beuefit may be expected to
have a higber respouse rate, wbich hns also not bee$ sfudied. buf csn be esfimafed to be 400/o
lrased on a rechallenge study of ipilinnunab [47].
A total of approximately 50 patieuts treated at the MTD of IL-2 + pembrolianmab rvill allow
us to estiumte a point esfimate of the tsORR and 950,4 conficleuce interual (CI) as below:
78

Protlnct: Penrbroliaunab
Protorol/Amendmeut No, :
lf the BORR is
The 95% Cl willbe +/-
Limits of g5% CI will be
a9oh
11.3%
{8.9 - 31.3o/o}
SAoh
13.0%
(17.0 - 43.0o/o)
40o/o
13.99o
(28.1* 53.9%)
5OVo
14.1%
t35"9 - 64.10/6)
lfr/e will deem this approacb uredtorious of firrther shrdy iu a mndomized hiat of the
combhation versu$ pembrolizrunab alone if toxicity is acceptable and
r If the BORR is 30yi, or rlore" or
r If the coulplete rery)ul$s rste sxceeds ?09{, or
r Ifthe I ye*roverall survivslrate exceed* g0{&.
8.6.33 Subgroup Andy*i* of primrry Endpoint:
BORR witrl be analyzed by the followiug characteristics known or suspected to *ffect elinical
outcoures:
r PD-LI positivc vs. negative
r B-fuqp u$tated v*. wild type
r Prior treafnreut with chec$oint inhibifor vfi. uot
r ECOG 1vs.0
r LDH elevated vs. nonnal
r Metastases linrited to skin, Ipnph nodes, and lungs vs. other distaut nretastases
8.7 Ana$slsof,SncordcryObjcctivcs
The secondarJr objectives are to ctraracterize the safr1y of IL-2 ia doses rangiag up to the FDA-
approved dose when adrninistered in combination r.vitir pernbroliaunab, aud to characterize
cliuical eudpoints, itcluding overall flrrvival, progresrion-&ee survival, t - and 2-year sruvival.
The frequeney of AEs aud SAEs willbe recorded" In addition, d^nta on the iupatieut coruse will
be sum&ariz.ed, includhg th* duratioa of hospital stay (in days), and the need for select
int*rventioas (hefffer to a hig&er level of .*r*, ,oe *f *us*p*r*or, o, use of, supplemental
o:rygelr} will be srrmryarized"
Clinical fiIea$ures of efficacy will be described, includiug overall stuvival, progressiou-fue
survival, need for additional therapy.
Descriptive statistical will be used, except rvhere otherwise specified. Coatiuuous variables
wi! !e pre*ented hy surnmory st$i*tics (such as msail, med.ian, standard eror and g0o/o CI)
*{ tb* eategorical variabl*s by frequeney distrtbutisns (i.e., frequency couats, percertages
aad 900;6 CI).
79

Pr"oduct: Pembroliaunab
Prof ocol/Amendrnent I'o, :
80
8"8 Aaalyris of ExplomtorA Objertiv**
Evaluaiiolt of irnrnunological responses rvill be primarily bnsed on the brendth aud magnit*de
of cellular respouses. The &equency of hunor specific T cells and repldatory cells incltrdiug
cD4+ Tregs and effector cDg+ witt ue rneasured pre-treafuirent and various days post-
treatrnent hr the hunor aBd peripheral blood. Tre*turent lfdbct for each patient wilt be lreasured
as paired dilfererces tk*tf:* 
and post measurements of these pararueters at variogs times.
Tranxfomratior ofthe datr wili beperfonned irappropriat , -* r"L tra&smr$BiioJ,* andhence
treatrneut eflbct will be expressed on a log scale.
8.9 Enrly Stopping RuIe for Toxicig
There will}e two pla&ned mferiur andyses for cotsideration of ear{y trial tenninatiol- The
DSMB will eval[ate ttrlJoxicltr data after the first t5 pntients are eurolled aud again after the
first 35 patienfs are emolled" If there nre >2/I5 or >*ri:-patienis with ntrs or sAEs of spscial
Interest, the shrdy wrllle placed on hold fbr coasideration of tenuination or nn a*en&nert to
fcrelse the safety af the trial. The DSMB has fhe "-txr"riry;; halt acerust to the stuoy at any
time for conceu$ over unacceptable toxicity or rrraeceptadlerates of destl].
9.0 LABELINC, PACKAGING, STORAGE AND RETURN OF DRUCS
9,I Pembrslizumtb
9.1.I Investigntionnl prsduct - pembrolizumab
Merck will provide peurbta,lizruuab. Padicipating sites rvill receive shiprnents of
-uii riiji i-r; i 7i ir-r,ri r rirr'.. ri., i.^r' 
J
The investigator shall take responsibiliry tbr aud shall take all steps to uraintain appropriate
records aad ensure appropriate supply,- ltorage, handling, distribution aud ruage of
inYestigational producf in accordan*i *itr, flri protocor ira any applic*ble laws and
regulations.
clinical Supplies rvill be providecr t yI 
su,u,arized belolv:
To request drug supply of pembrolizumab, use the Merck Drug R*quert Form"
9.1.2 Packoging sntl Lsbeting Information
Clinical supplies will be affixed with a clinical label iu accorclance with regulatory
requirements.
Protluct Nnme & Potencv
Perubrolizrunab I 00 mgl 4mt
Dosage Form
Soltrtion fur hrjection

Product: Pentbroliaunab
Protocol/Amtntlment No. :
9.1.3 Clinicsl Supplies Di*closure
Thi$ finl iu opeu'lebel; therefnre, tlre xu$ec! the trial site perxouuel, the Sponsor aud/or
desigpee *re uot bthded to heatrnent. Dnrg ideutiq, (narue, s*ength) is included in the label
text.
9.1.{ Storage sna} Htndling Requirements
The dnrg product mtut be stored turder refrigerated eouditions (2'C - 8oC). The drug product
a$er recnustitutisu witlr sterile water for injection nnd tbE liquid dnrg product are a clear to
opalescent solution which rnay coutain proteinaceous and extranious particulates. The
reco$titufed lyophilized product aud the liquid product are inteuded for IV admiuishation.
The reconstituted drug product solution or the liquid dnrg product can be ftuther dihrted with
normal saline ful fV contairers smde of polyvinyl chloride (PVC) or uou-PVC uraterial.
Reconstituted vials should be iurmedi*tely used to prepare the infusion solution in the IV bag
and the infirsiou solution should be irrunedinfely adruinistered. If uot used inunediately, vi*li
mrd/or fV bags nray be stored af 2-8 "C for up to a cumulative time of 20 hours. If refrigerated,
&e vials andlor IV trngs sbodd be allowed fo eqtrilibrate to room tenrperahue prior to
subsequert une. MK-3475 solutions may be stored at room temper*ture for a cumulative time
of up to 4 horus. This iueludes rooln tenrperaftue stor*ge of reconstihlted or liquid DF solution
in vials, room tenrperattue stornge of inftrsion solution in the IY bag aud tlre durstion of
infixion.
Clinical supplies must be stored iu a sectx"e, limited-access locatiou urder the storxge
couditions specified oo the label.
Receipt aud dispansing of kial medicatiou must be recorded by an authorized percou at the
trial site.
Clinical supplies may not be used for any pulpose other than ihat stated in the protocol.
9.I.5 Returns and Reconciliation
The investigator is recponsible for keeping aecruate records of the elinical supplies r,eceived
0'om Metck or designee, the amount dispensed to nnd refunred by the sulrjects and th* amourt
remai*ing at the conclusion of the hial.
Upon completiou or termination of the sfudy" all uuused audlor parfially used investigational
product will be de*troyed at the site per institutional policy. It is the Investigator's
responsibility to arrange for disposal of all empty containers, provided that procedrxes for
Proper disposal have been established ac*ordiug fo opplicable federal, st*te, local and
ilstitutional gnrideliaes and procedures, and provided that appropriate records ofdisposal are
kept.
81

Pr oduct: Peurbrolizruuab
ProtocrllAmetrdmstrt No. :
9.2 IL2
82
9.tJ Suppty
IL-? (Aldesleukin' Proleukin8) is * commerci*lly available prodnct (honrethe:ru) and is o1-
label fsr metaetatic rnelanoma. IL-? will be ol*ain*d thr*;sl, thr *o*[o*iuf'*6rr"
9.1.2 Storage, Preparxtion, *nd Admirirtrstior of IL-?
Reconstituted IL-? should be fixther dihrted with 5% Dextlose, USF. Do not nrix with saline
containing sokrtions- Recorxtihrted IL-? uray be clituted a$ uece$sary iu volu*res of 50 ml to
500 n{ with 5% Dextroseo USp. Wheu dituted for IV adrnfu;*pu,ion in 596 Dextrose Iujectiou,
UsP, in a plestic bag (e-g. Yiaflex, uranufacttred by Travenol Laborafnries, Iuc.,) IL-2 is
chemically stable for 48 hours at refriger*ted and roCI; temperafures, 2-30oC. Iutact vials are
stored in the refrigerator (z-s"C) protected &om lighf" Each vial bears ag expirution aat".
For dosrs rt 6$0,000units/kg:
Recansfituted IL-2 should be fruther diluted with 5od Dextrose, USp. Do not urix rvith saline
gsnfsinirg solutions" Reconstituted IL-2 may be diluted as lecessary ia volurnes of 50 ml to
500 r1rl witlr 596 Dextrose. USP to maiutnin a conecakation between 0.03 mg*nl, and 0.07
mglml (490,0CI0 urrits/el to 1,145.000 units/rnl). Whes dilgted for fV sdmioistration in 5%
Dexhose Injection" UsP, itr a-plastic bag (e.g. Yiaflex, manufachred by Travenoiiobrr"tori"u,
Inc',) IL-2 is chemically stable for 48 hsurx at re&igemted mrd roour tanperatrues, 2-30,C.
intacf fials are stored iu the re&igerator (?-8'C) piotected from light. ru*l "iut 
bears an
expiration date.
For dorer at 60,(}00 unitslkg
Coucenkations of Proletrkin below 0"CI3 mg/ml and above 0.07 urg/ml ftelow 490.000
turits/ml and above 1,145,000 ruritslml) have ihown increased variabili[ in d*g delivery.
Dilution and delivery of Proleukin ouiside of this coucentration rarge requires courpouuding
wi$ 0,' t it albumin (for example, I ml of 59o aibunrin added to 50 uri D:* bag before addiug
Aldesleukin (IL-2) (4S).
For doscs at 6,000 tnitr/kg
Colcentations of Proler:kiu below 0.03 mg*]& and above 0.07 mglxl ftelow 4g0,S00
.*itdml and above 1.14s"000 rmits/ml) bave shor** insreased varicbilii, io &xg delivery.
Dilution and delivery of Proleukin outside of this coucentration range requires compotmding
*i!t 0.. l% atrbwnin (for exaurple,0.5 rntr of 5% albrxnin added to ?i nii DsW lmg before addigg
Aldesleukin (It-?) (4S).

Product Pembrolizrunab
Pt'of ocoUAmeudmeut No. :
,.2.3 IL-t FormulntionlReronctitution: IL-I
FonnulationlReconstitution: IL-} (Aldesleukiu, Proleukius). please see the Iuvestigaiors
Brcchure for: th* complete phammcetrtical package inserl) is a courmercially available producl
(Prometheus).
The nredicatiou is provided as a lyophilized powder and a l'icl of rnedication is recorstituted
with l.?mg of Sterile Water frr Injection, USP, and the rezultant coacentrafion is 18 ruillion
ruld.
Diluefi shordd be directed againsf the side of the viat to avoid excess foaming" Swirl contents
gefiIy uutil completely resolved.
Do ast shake.
Since vials cont*in ro preservetive, reconstihrted solution should be used withiu 8 hours.
1I}"0 ADIIIIM$TRATIVE AIID REGULATORY I}ETAILS
l0.t Con{identiality
Subjects' ideltities, rames or any identifying characteristics will not be disseminated iu
publicatious, nor made public. The dats forms will be de-identified. meaning that fhe patients
identiffing infonnation $/ill be matched to the research nuulber, in a reparate file.
l0.l Compli*nce rvith Fir*ncid Dirclosure Requiremsntc
The Principal Investigatot aud Sub-Investigators must comply witb applicable frderal, state.
and local regulatious regarding reporting aud disclosrue of conflict of inferest. Conflicts of
iuterest may arise frour situations in which financial or other personal consideratious have the
poteutial to courpromise or bias professional judgguent and objectivity. Conflicts of interest
inelude but are aot limited to royalfy or c.onsulting fees, speakiug houoraria, advisory board
appoinmenh, publicly-traded or privately-held equifies, stock optious, intellecfiral properfy,
and gifts.
10.3 Compli*nce with Law, Audit lnd Debnrnnent
By siguing this protocol, the investigator ntrrees to eonduct the tr:ial in an effrcient aud diligent
ma$fier aud in confcnuance r'vith this protocol; geuerally accepted standards olGood Cliaical
Practice (e.g., lntenmtional Conference ou H*nnonization of Teclurical Requiremeuts for
Registration of Pharnraceuticals for Hutran Use Good Clinical Practice: Consolidated
83

Product: Pembroliarrnab
Protocol/Arnenelrnent No. :
Trial doctxnentation will be prourptly and fully
t{roo request aud also shall be made available ;
copyiug. review ancl audit at reasonable tirues
84
Guideliue afid other gerrerally accepfed staudards of good clirrical practice): a'd all applicable
federal, state and local lar.vs. nrles aud regulatiorx relating to the concluct of tlre slinical trial.
If an aurendment substantially alters the sfudy design sr ilrcreases the potential risk to the
subject: (1) the coffieuf forur tnrst be revised aud suburitted to the fnn for review and
approvaUfavorable opinion; (2) the revised fomr urusf be rxed ts st'tafu consent from subjects
crmently eurolled in the study if they arc affected by the amerrdrnent: aud (3) the o"* fot*
must be used to obtain consent from uerv subjects prior to enrollmeut"
If the revisiou is doue via an a*rrinisbative letter, investigatom must inform their IRB"
The investigator also agrces to allow monitoring, audits, IRBfrRC reviery and repprlafory
authority inqpection of hial-related docume,uts aud procedrres aud provide for direct access to
all trial-r*latetl source data and docuuents.
The investigator agrees not to seek reimbuse.urent frour subjects, their insurance pror,:iders or
from government proggxms for procedtues iucludEd as part of the hial reimbtused to the
investigator by the Sponsor.
The investigator shall prepare and ruaintain courplete and acctuate trial documentation in
courpliauce with Good Clinical Practice standnrds and applicable federal. state and local laws,
nrles audregrrlations; and, fior each sudect participating in the trial, provide all data, and, upon
completioa or tenuination of the clinical hial. submit my other reports to the
Sponxor as required by this protocol or as otherwise required puruant fo auy aggeenrent with
tlre Spousor.
disclosed to the Sporrsor by
nf the trial site upon request
the investigator
for inspection.
by representatives

Product: Peurbroliaunab
Protocol/Amendmert I{o,:
regulatory authorilies. The investigatCIr agree* fo proulptly take any reasotrable steps that are
requested by the Sponsor as a restrlt of an audit to cule defrcieucies in the trial docruuentation
atrd rvorksheets/case repcrt forms. The investigator urust uraintail copies of all docuurentatio,
and records relating to the coaduct of the trial in compliance witti all applicable legal and
regulttoty requirerrents. This documentation ifieludes" but is nof limited to. the piotocol,
worksheetr/case report fonns, advertising for sudect parricipation, adverse event reports,
subject sotuce datao conespondence with regulatory iuthor*ies alld IRBsIERCs. cousenr
fomr1, investigator's cnrrieula vitae. monitor visit logs, Inboratory refsreuce range$, laboratory
certificatiou or quality conkol procedures aud laboratory directoi curricuhun viiac. By sipriug
this protocol, the iuvestigator a!f,ees that documentafion shall be retaiued rrntil at least 2 years
after the last approval.of a srarteting application in au ICH region or mtil tlrere are no pepd.ing
coutempl*ted ruarketing applicatious in an ICH region or turtil at least 2 years have-elapsei
silce the formnl discortinuation of c.linicnl developmeirt of the invesiigational product.
Because the clinical development nsd marketing applicatio* proee$s G variabie. it is
auticipated thst the retention period can be up to 15 yeflr$ or longer after protocol datab*se
Iock. The Sporsor will determine the rvinimum retention period and notify the investigafor
rvhen docuuents ruay be deskoyed. The Spousor rvill determine the urinimum retention plriod
qrd upon requsst. will provide guidance to tlie iuvestigator rvher clocumeuts no lougerneed to
be retaired- The sponsor also recogrrizes that documeuts aray ueed to be retained lbr a louger
periotl if required by local regulatory requirenrents. All trial documeuts shall be nrade available
if required by relevaut regulatory auflroritjss. The iuvestigator unrst corrsult with and obtain
written approval by the Sponsor prior to destroying irial aldlor subject files"
ICH Good Clinical Pmctice guidelines recommend tlrat the invesfigator iufonu the sulrject's
prirnnry physician about &e subject's participation in the hial if tlre srrbject has a prirnary
physician and if the srrbject a8rree$ to the prirnary physician being infolned.
The investigator will prourptly infonu the Sponsor of any regulatory authority inspection
conducted for ttrris hial-
Persous debailed &om conducting or working on cliuical trials by any corut or regulatory
authority rvill not be allowed to co*duct or rvork ou this Sponsor's trials. Tbe investigi-tor wiil
irnmg{lltsly disclose in writing to fhe Sponsor if any person who is involved in conducting the
trtal is debarred or if any proceeding for debanueut is pending or. to the best of the
investigator's hrowledge, tlueatened,
In the -eveat tlre Sponsor premattHely te$rdoafes e particular trial site, the Sponsor will
promptly notify thst trial site's IKB.
The rights, safety, and well-being of the shrdy subjects are fhe most inrporlant consideratioas
aud should prevail over interests ofscience and society.
10.4 Isffies rr.ith Minorr
For miaors, accordiug to local legislation, one or both parents or a
85
representative urust be iufouued of the shrdy procedures ond must si

Product: Penrbroliaunab
ProtocollAmendrneut No. :
fonn approved for tlre shrdy prior to clinical study participation. The explicit wislr of a minor,
rvho is capable of frrnring au opinion and assessitrg ihis infonuation to refirse partieipation
iu. or to be withdrawa frorn, the clinical shrdy at ury tiure should be cousidered by &e
investigatar.
Minors who are judged to be of an age of reason must also give their writterr assenl.
10.5 Complisnce with Trirl Registration rnd Re*ults Posting Requirements
Under the tenus sf the Food and &ug Adrniaiskation Modemization Act {FDAMA) urd the
Food and Drug Adnriniahation Amendruents Act (FDAAA), the Spousor of the trial is solely
reqpoasible fbr detemrhi$g whetlrer fhe trial arrd its results sre subject to the requiremeufs for
submissionto the Clinical Trinls Dafa Bank, http:llwww.clilicaltrials.EioY. lpfogetiouposted
will allow subjects to identi$ potentially appropriate trials for their disease conditions aud
pursue participation by calling a cenhal contact mr$rber for fixther infonnatiorr on appropriate
trial locatioas and trial sife contact infbmratiot.
10.6 Qu*lity $ll*nagemcnt Sy*tem
t0.6.1 Doto $rfety Monitoring Bo*d
The Rutgers Cancer lnstitute Htunau Research Oversight Coururittee is responsible for arurual
data and safety urouitoring of investigator iuitiated phase I and II, thempeufic interveutional
studies thet do not have an ildepeudeui Data Safety Monitortng Board (DSMB)" The prinary
focus of the HROC is review of sa{bty data, foxicities ftnd uew infonnatiou that ruay affect
subject s*fefy or effrcacy. Annual safety reviews iucludes trut rray not be lirnited fo review of
safety data, enrotlnrrnf status, stoppiug n:les if *pplicable. accnral, toxicities, refererce
literahre, and iuterim analyses as provided by the sporisor-invesfigator. Tke HROC iu concert
rvith the Qlalify Assurauce Monitoring Tearu oversees the conduct of Rutgers CINJ cancer'
related, sponsor-investigatar tlerapetttic intervention and prevention iutervention studies that
do not have an extemal monitoring plan. ensruiug subject saftty snd that fhe protocol is
coaducted, recorded and reported h accordance with the protocol, stauding operating
procedue* (SOPs), Good Clinical I'ractice (GCP), and applicable regulatory requirements.
10.6.2 Monitoring
86

Product: Pembroliaunab
ProtocoUAmendment I{o. :
trial network that has conducted over
ovel.
past ?0 years. All sites have high-dose IL-2
experience and must conunit to accrual of at least 10 patients each year'. Thus. the mernbers of
t&e CWG represent a eroup of nstional expsrts on the clinical use of IL-2. The CWG bas sn
established monthly telecouference to discuss protocol staflrs, sulrject accnral adverse events
and other aspects ofeach kial.
10"7 Rogistrrlian
r Registration: Any subject that has signed the conseot will be entercd into OnCore. A
copy of the consent will be uploaded hto the Doctuueats section.
c Enrollment: Once eligibitiry has been corrlinned- the corupleted signed and dated
eligibility checklist subjects will be euolled ihrough OnCore. A sequence mrmber
(subject study ID) will be generated at the tinre of ennrllment, this is the point the
patieut is considered on study. Participating centers will upload source docrunents for
baseline and screening assessmerlts into OnCore.
Pafients will not ttari protocol treatment prior to regisfration.
Trial treatrnent should begiu withio l0 days of registratior or as close as possible to the date
87
on which toeatme*t is allocated/assigped.

Product: Peiubroliaunab
Pr otocoVArnendment lio. :
10.8 Datn ${unagrrn*nt
I{}.fi.I Study Documsntstinn
Study docunrerttation includes but is not limited ts souree docruuents. case report forms,
ntonitoring logs' appoiuhnenf schedules, shrdy tearu correspondence with sponsor6 or
regulatory bodies/coruuittees. and regrrlatory docunerrts thsi cau be found in the DCI-
urandated "Regulattxy Binder*, which includes but is nat liurited to sipped protocol aud
, approved and signed informed conseut form$, FD.A Fonu tS?2, Cef aud CLIA
laborafory certifications, and cliuical supplies receipts arrd disfiibution resords"
Source docunerts me nriginal records that contain source data, which is all infonnation in
original records of clinical fiudiugs. observations, or other activities in a clilical hial necessary
for the reco0stnrctiou aud evaluafion of the trial. Source docnments include but are uot limited
to ho*pital records, clinic.cl aud office charts, laboratory $otesn meproranda, subjects' diaries
or evaluation clrecklists, plmmacy disperuiug recoi&, recorded datr fiom autourstcd
instrtuuents, copies or transcriptioas certified a*er verification as beiug u***utu copies,
microfiches, photographic oegatives, microfil,r or mngpretic mediq *-ruyrl subject files, and
Scgrds $qt *1 the ptnnmcy, at the laboratortes and at medico-teclrnical departmeuts involved
ifir} the clinical trial. When possible, the original record shorrld be retained as the souroe
docu[ent" However, a.plrotocopy is acceptable provided thst it is a clear, legible, aud a11exact
duplicatiolr of tlre original documeut.
10.8.1 Cnxe Report Formr (CRf'r)
The elec&onic CRF stored in OncoreQ will be the prirnary dats collection tlocunreut for the
study. The CRFs will be updated in a timely mauner following acquisition of oerv sorrce data.
OnIy the key persorurel delegated on the delegatiou of authoriry log are pennitted to make
euhies, changes, or correetions in the CRF.
An arrdit trail rvill be rnaintainsd autometicolly by the elecfronic CRF urnnageruent systa,. AII
userx of this system will complete usar trainirrg, as required or appropria*for regulatiops.
r0.[.3 Data ll{ansgernent Froc*durcs snd Drfa yerllication
Usem of the electrcnic CRF will have access based on their speci{ic roles in the profocol.
Completeuess of entered data rvill be checked aufouratically by the eCRF system. aud userx
rvill be alerted to the preserce of datn incousistencies. Additionally, the data ma*ager ad
ptgJTt ryansser will cross-refereuce the data to veri$ accuracy. Missiug or irrplausiSle data
will be highli8}ted frr the PI requiring appropriate responses (i.e. cin{innatiog of dala,
coffection of data, conrpletion or confinnafiorr tlmt data is lrot available, etc.).
The database will be reviewed and discussed prior to datatls$e closure, and will be closed only
after resolution of all rssalning queries. fui audit trail will be kept oi all subsequeot changes
to the data.
88

Product: Pembroliaunnb
ProtocoVArnendment llo.:
10.8.{ Study Closure
Following coulplstioe of tbe *ludios, the PI will be rerporsible for eusuring Sre follouriug
activities:
- Dak clarificefion aud/or reuolution
- Accounting. recouciliation, and destruction/retrun of used and unused shrdy dmgs
- Review of site study records for corrpleteness
- Shipment of nll r*mairdug l*bamtnry samples to &* dexi$ratsd laboraiories
10.9 D*t* Srfety Monitcring Phn
89