Moving PD-1 Blockade With Pembrolizumab Into Concurrent Chemoradiation for Locally Advanced Non-Small Cell Lung Cancer
Phase: PHASE1
Conditions: Stage II Non-Small Cell Lung Cancer, Stage IIIA Non-Small Cell Lung Cancer, Stage IIIB Non-Small Cell Lung Cancer
Sponsor: Rutgers, The State University of New Jersey

Official Title: 
Moving PD-1 Blockade with Pembrolizumab into 
Concurrent Chemoradiation for Locally Advanced Non-
Small Cell Lung Cancer (Multi-Center) 
NCT number: 
NCT02621398 
Document Type:  
Study Protocol  
Date of the 
Document: 
10/21/21 
 

$. conlidantisl
(loncurrent Chenrortdiation
SPO)iSOR:
\\'ith funding sup
TITLE: Nloving PD-l Blockade with Pembrolizumab into
for Localll'Advrnced Non-Small Cell Lung Cancer
IND XLIIIBER: 116,833
EurlraCT NLTIIBER (Stutlies in furope only):
Version Date: 28-JtrN-2018
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Princioal Inlestisntor :

Protluct: PerirLirolizurnab
Protorol/Amrntlrneut so.r f 
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C contidtntiel
1.0 TRIAL ST'}I}IARY
2.0 TRIAL DESIGT
2.1 Trial Design
This is a non- ranclornizecl. ruulti-site. opeu-label. Phase I trial of pembrolizrunab (t\'IK-1475)
il sulrjects rvith locall,v aelvanced or inoperable non-sruall cell lturg cancet'. who have not
received prior svsternic t:lteurotherapy or prior tltoracic radictherapy.
The mait goal of this trial to nssess rat'ety and tolerabilit"v of the comtriuaticu of
perntrrr:lizuruab rvith cruative iutent cheuu:radiation rherap_v*- tbr rr:u-operable uou-surall cell
hurq cancer'.
1
Abbreviated Title
A Phase I Siutly of Perrrbrolizrur:rab {lv'lK--l4?5) aud Concrrn^ertt
(lhemoradiariou for Nou-Srnall Clell Lrurg Cancer
Trial Phnse
I
Clinrcal Lrdicatiorr
Iloperable Non-Srnall Cell Lrurg Clrutcer to be treated u'ith
Cheuroradiation
Trial Tlpe
Lllen'entiorlal
Type ofconfiol
No treatureul cofitrol
Ror.rte of atlrrrilistrrtion
hrtratenour
Trial Blmt{ilg
Treatrneut Groups
),iuurlrer of tlial *rt{ects
l.l-,1i)
Estirnated eruolhnelt periocl
Octolrer ]01 5- \l*rch X] I i
Esriuratecl chu'atrol of h'ral
Tlre trral u'rll rerprire approxiutntell, l8 ntortrhs tr"ortt (lte ti.rue fhe fir'st
subject rigns the utbrured colrseut uxil the lnst subject'* last risit.
Duralio:r of Participatiorr
Ench srrb.iect u'ill panicipate in the trial li'om the tir:ue the Itforrued
C'or$errt Fonn (IC:F) is sigued tluough the tinal toltact. Each eligible
pafient u'ill rec*lve heatruerlt as per the trial derigr. Atier the errd of
flearrleut. eaclr *ubject r,ill follorred every I lr,eeks for adverse eletrt
nroriitoring or before tire initiation of trelv anti-cancer ther"apy rvhiclteter
conres first. Serious el'ents aud elelts of clitrical irtterest rvill be collectetl
tbr 9Q dayr atier tire end of treafiuent. Subjectl rvho discoltirrue flor reasottx
olher rlran disease progressiott rtill har,e post-trtnfulent tbllou'-up for
disease $tnnls e\"ely 1l weeks i:14 daysi iu the lirrt l,ear and ever-v 16
u'eeks (-r I -l da1"s) atier yenr 1 turtil clisea,se progn'ersion is corrtinued by the
iur:estrgntor. a uorr-shrdy treallnerlt is initiated" tollselll is u'ithdrarvn. urtil
tleath. or becolrirrg lost t,r follou'-up. All subjects s'ill be follorved lry
telq>lioue for oterilll *tur,ilal eten lf rreeks 1,+ 7 clayr) rurtil death.
u'ithdrnrval oi corrselt. nr the encl of the trial-

Ploduct: Peutbrohzrmtab
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ProtocoljAmeudrneut ao., I
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Conlidontial
Approxirnately 30 patients urav be eru'olled aucl rvill provide newly obtained tbnnalin tixed
palatlin ernt:edded (FFPE) huuor biopsies for PD-LI detennination tr-v itmmmohistoclteuristry
(IHC') PD-Ll positiveiueuative population is cletiuc:d as snbjects rvith PDI--Ll assay restrh
higherilower than the PD-Ll cut pr:irrt.
All subjects uurst have rrreasuable disease ba-sed orr MCIST l.t. All patients rvill receive
perntrrr:lizumab regardless of PD-L I stahrs. Sudects rvill be acluriuistered peurbrolizrunatr as
per: the study schenla. stalting at a dose of 100 mg and tnoving up tr:i ?00 lu€t evelT tlree rveeks
(Q3W). begirururg atier corupletion of chemolacliafiou and then incr:rporating peurbrr:lizunab
with cheruoracliatirin fl$ pel'the Phase I trial design.
Subiects rvill [:e urouitorecl for toxicity tluough visits occruring rveekly druing radiatiou
therap-v ancl every rveek rvheu receir,iug, pernl:roliaunab alone.
Subjects r.vill tre evahmtecl at 9 rveeks (. 7 daysi nfter the tjrst dose of peurbrolizutuab ancl
ever1, 9 rveeks thereatler rvitlr rachogmphic iruagurg to assess respon$e to lreatmeut. Sutrjects
rvill reruaiu on treatrneut up to 18 doses of pembrolizurnatr. For lollor.v-up after
penrl:roliaunab. sulr.jects rvill have iutaging perfomred evety I2 rveeks thereat]er. Lrrages will
be reviewed by the stud-v iuvestigatols using the Response Evaluation C'riteria il Solid Turttors
(RECISTI L I iincl the Irruuune Relatecl Resporme Criteria (irRC:) tbr detenniuatioti of local
rcsponse or ruetastatic prr:gressiou. The investigator may choose to treat be-voud RECIST l.l
clefined prcgression in sutrjects considered to tre deriving clinical benetjt ard rvho are clinically
statrle.
Adverse erreuls u.ill tre monitr"irecl tluough the trial ancl Sraded in severit-v according to the
guidelines outlines ut the NCI Conuuou Temiinology C'riteria tor Adverse Events versiott.tr.0
(CTCAEv4.0). Treaturent rvith perubrolizrurmb rvill continue uttil documeuted disease
proglessiou b.v the inr"estigator. ruracceplable adverse e\.ellt($). intercrm:ertf ilhress that
prevents further aihuinistratir:u of trcatulert, ilvestigator decision to rvithch'ar,v the sulilect.
sutiect rvithdrarvs corlsent. pregnaucy of the subiect. uoucourpliance rvitlt the trial treatrnerlt
of procedure requireurents. coulpletion of i8 doses of treatmeut with pembrolizuuralr or
nrirninistrative rea sorts.
Sutrjecfs. rvlro attaiu an iuvestiqator-cleteruinecl cr:rtfirrrrecl complete response (CR), should
contigue tbr l8 doses oltreatrnent. Subiects rvho discontinue for l'easollri other tltan disease
progression or tntolerabilit,v. or rvho discontiuue aller attaining a CR ura,v be eligilrle for one
,vear of r etreatment afler the_v have experienced radir:graplric disease prr:gression. Tlie decisicru
to retreat tvill lie at the cliscretion of the irrvestigator only if no callcer treaturert wa$
acluinistered since the last dose of peurllrolizurnab. the subject still ureets the salbtv parafietels
listed in the Inc-hxion,Exclusirin criteria nud the trial remainsi open.
Afler the end of treatment. each subject rvill be tolk:rvecl for toxicities every S tveeks (l 7 clays)
comes tilst. Serious eveuls alll eveutt of cliuical interest lvill tre coll
(for adverse event urouitorinq or befirre the initiation of nerv anti-cancet

Plotluct: Petttbrcilizrntrab
ProtocollAmeudment So.: f 
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C 
Confidantial
the e1<1of treatureut or 30 days after the end of treatrrrent if the subject initiates new anticancer'
tfuerapy. u'hichever is eariier. Subjects rvho discoutimre t'or reasorls other than disease
progi'o,ri.,,r, rvill har.e post-treatrnent lbllow-up for disease sratus ever-:r l2 rveeks (Jl4 clays)
i, tt" tirst year aurl even' 16 rveeks ltl4 days) alier year I until disease progression is
confinued b!, the iuvestigator, a non-stucly trefltmenl is initiated. collsent is rvithdrawn. turtil
cleath. or becr-:rpilg lost to tbllow,-up. All sul{ects rvill be tolloi.ved by telephorte for overall
sruvival until death, rvithdlar,val of conserrt- or tlte eud of tlre tr:ial.
The primarv r:bjective of tiris shrcly is to evahmfe the safbty and toxicity r:f pernbrolizruuab irt
cr-.lrtrinatiou rvith clefilitiye clrem6radiation tlrerapV for irroperable or locally advanced nott-
surall cell lung cancer.
2.2 Trinl Diagrtm
The trial design is shorvn iu Figure I
Figtue I Trial Desigu
3.0 0BJECTM(S) & HYPOTHtrSIS(ES)
3.f Primary Objective(s) & Hypothesis(es)
(l) Ot_aective: To assess safery* aud toxiciry* of PD-l inhibition rvith peurbroliztuuab rvith
colcurreut cheuroradiation tlrerapy ftrr nort-operatrle, k:cally advarrced non-surall cell lrulg
caucet'
Hplothesis: Inh'avenous adrniuisuation of pembroliztutral: wiil be safe and tolerable when
incorporated into conctuaent chernoradiatiou therapy
4
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t" | '
ffi
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W

Protluct: Peurbt^olizurtmb
5
Protocoli'Ameutknent -o,t I,,
C 
(onriderntial
3.2 Seconthry Objective{s) & Hlpothesis(es}
(l) Objective: To evaluate local and clistaut uretastasis-fi"ee sttrvival, progressiorr-free and
r:velall survival with the additir:l of peurtrrolizruuab to cheuroradiofherapy
Hpothesis: The addition of pembrolizunab to cheuroraeliatiou therapy rvill result iu
iuprovetl progression-fi'ee stuvir,al. overall sm'r.ival. an<l local an<l uretastasis fi'ee surival
rates over historical coulrols
(2) Objective: Tr: evalunte the rntes of pneuuronitis thnt ruay result fi'otn combilation
perutrrolizurnatr and chemr:radiotherapy
3.3 ExploratoryObjective
(l) Objective: To assess rvhether PD-Ll stanx on irruuunohistochemistry is predictive of
response to perut'rrolizrmratr rvhen combirtecl with clteuiot'ndiation therapy
Hlpothesis: Due to the potentiatiug el'lects of racliatiou therapy ou the inuurure systen). we
hypothesize the iurproved response rates conrpar"ed with cheruoradiation alone rvill not rely on
PD-LI positivitv alone. \\re expect PD-Ll patierrts to respond lretter than PD-Ll r]eq,ative
patierrts compared to cheuroradiation alore.
(?) Objective: To RSses.s T cell (C'D8+T cells and CD4+FoxP3+ regulatory cells) responses
al u,eeks l. 3. 6 cluriug cherrrorarliatiou therapy aud t"refrrre each adrniuistlaliorr r:f
peurbrolizurnatr tor cycles l. 3. 3
.I.O BACKGROUND & RdTIOIYALE
4.1 Background
Retbr to the Investigator''s Brochure (lB)lapproved labeliug for detailed trackground
infonuation ou IUK-3'175.
.{.1.1 Pharnraceuticnl and Thertpeutic Blckground
The inportance of intact irunture sruveillance in controlliug outpu'owth of neoplastic
transfcrmtatiou ltas beeu knorvn for tlecades. Accuurulating evideuce shows a con'elation
behveeu trunor-infiltratirrg ll,urphocltes (TILs) in cancer tissue and favorable prog.nosis in
varir:us utaligurancies. hr parlir.:ular. the preseucr' of CD8 i- T-r:ells aucl lhe ratio of CD8+
eff'ector T-cells ' FoxP-l* regulator.v T-cells seems to conelate with irnproved prr:gnosis aud
Iorrg-tenn sruvival in nrany solitl tumors.
The PD-l receptor-ligancl interaction is a maior patlnva-v hijacked by fumors to suppress
inunture conhol" The rronual tiurctiou of PD-1. expressed on the cell stu'face of activated T-

Ploducf : Petutiroiizunmb
Protocol/Amendrneut -o., I 
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C 
Confidential
cells rucler healthy conclitious. is to dorvrr-rnodulate unwanted ot excessive luulltule responses.
ilclgcliug autoirmmure reactious. PD-l {encoded b-v tlte gette Pdcdl) is an Ig superfauril.v
lrentrel relatecl to CD28 and CTi-A-.1 r.vhich has been shorvn to nesatively legulate autigen
receptor signaling upon engaseulent of its ligancls (PD-L I andlor PD-L?). Tlte stntchu'e of
,o,rrir,* PD-l has been resol"i.ed. PD-l ancl fauril-v rt.eubers are type I trarntlrembrane
glycoprotein^s corrtaiuing arr Ig \.'ariatrle-t-vpe (V-gpe) donrain responsible tbr ligand triudurg
ancl a cyoplasuric tail rvhich is lespousitrle for the binding of sigrraling tnolectiles. The
cytoplasuric tail of PD-l contaius 2 t-vrosiur-r-basecl siglaliug rrrotit,s. an irtntttutoreceptot^
tvrpsine-lrased inhibitiolr rnotif (ITI\,1) aud an inuuunoreceptor ry'r'osite-based srvitch motif
(ITSlv{t. Follorviug T-cell stirmrlation, PD-l recntits the tw'osirte phosphatases SHP-l and
SHP-2 to the iTSN{ motif rvitlun its cytoplasrrric tail. leadurg Io the dephosphr:rrllation of
etl'ector nrolecules such as CD3(, PKC0 and ZAP70 w'hich are involved in the CD3 T-cell
sigualing cascacle. The mechanisrn by r.vhich PD- I tlolvn utodttlates T-cell rt''spollses is similal'
to. but distiur:t li'om that of C:TLA-4 as both rnolet'ules regulate an overlappitg set of siprnaling
proteils. PD-l was showu to L:e expressed on activated lyrnphoc-vtes inclucling peripheral
CD;l+ aucl CIDS+ T-cells. B-cells. T regs and Natural Killer cells. Expt'essiou has alsr: been
shorvn cluring th_v*uric developmeut on CD4-CD8- (dorrble negalive) T-cells as lvell as stttrsels
6f nracrophaqes and dendritic cells. Ihe ligarxis ibr PD-l (PD-LI artcl PD-LI) are
conslinrtivelv expressecl or can be indrrced in a variell' of cell t)'pes. incltrdirig non-
hernatopoietic tissues as rvell a.s in vnrior$ nuuors . Both ligalds ar^e 0?e I transrneurbrarte
receptors contaiuing troth Ig\:- antl IgC'-like dourains in the extracellular regioti and coutain
short cl.toplasruic regions with no krowu signalirrg motifs. Bilding of either PD-l ligaud to
PD-l inhibits T-cell tctir,aliou triggered llu'ough the l-cell receplor. I]D-Ll is espressecl al
lorv lerrels on various ttou-hematopoietic' tissttes. ntost notabl-y ott vascttlar enclothelitun.
rvhereirs PD-L: profeiu is olrl1, cletectabl-v expr"essed ou att(igen-preselttittg cells lburcl iu
llruphoid tissue or cluonic intlanuuatory envirorunents. PD-L2 is thought to coutrol inuuune
T-cell activation in ly111pl1o1,1 ergans. rvhereas PD-Ll selyes to dampeu tutrvanartted T-cell
frurctiou in peripheral tissues. Ahhough healthy olg1alls express little (if any) PD-L l. a varietl'
of cirucers rvere cleruon.strated to expreiis abunclaut levels of this T-cell iultibitex. PD-l has
treen suggested to regulnte tlrrrlor-specific T-cell exparrsion in subjects r.vith tuelattomn (N{EL).
This suggests that the PD-lr'PD-Ll patlrrval'play's a critical role in nuuor itmnture evasiott and
shoulcl be cousidered as an attlactir.e talget tbr therapeutic itttet'r'entiolt.
Peurl"rrrllizuruab is a potellt ancl highl-v relective lmrnauized mortoclonal autitrocly (uAtr) of the
IgG4rkappa isot-r'pe clesigrrecl to clilectll'block the intel'action betrveeu PD-l an<l its ligalrds"
PD-LI antl PD-L2. Kel,tnrdarM (reurbrolizruuab) has recently treen a1:1:roved iu the United
Statecl tor the treatmeut of patierrts u.ith rurre"sectable or rtetastatic tuelanouta ancl disease
proglessiou lbllo*'ing ipihurrunatr ancl. if BL{I] \'600 ruulatiou positive" a BILA.F inlibitor.
1.1.2 Preclinicrl nnd Clinicnl Trinl Data
Refer fo the Iuvestigator's Brochtue for Preclinical aud Clinical data.
6

Product: Peutblolinurtatr
Protocol/Atnendment so., I. 
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c$ntidantilrl
4.2 Rationale
4.2.1 Rntionale for the Triql :lnd Selecterl Subject Popul:rtion
Iu 2014. an estimated 214.1 l0 inclivitluals rvill have lreeu diagloseti rvith luug catlcel', anel tliis
diagnosis will result in approsimately I 59.260 deaths( 1). The elevated ruortaliry* of this clisease
suggests both a poor biology and inacleqlmcy of available therapies. At presentatiou. most non-
small cell lung caucer (NSCLC) cases are uredically ir:ope'rable or have umesectable disease.
Locally aclvanceri clisease and metastatic disease each accortnt fbr about 30o.''o of all ner'v
diagrtoses-irnpl-vingthatresectablediseaseisaruinoriryofNSC'L('("l200'6X2)'N{auagemettt
of rueclically inoperable aucl locally aclvanced NSCLC relies ott radiation therapl as tlte
primarl' urr:daliry of therapl' aud is usnally' cotubined with cottcrulent chemotherapy. wbich
has shou'n the greatesl prondse wilh r:egard to averall sruvival in nttnterotrs rattdourized trials
(3.4).
Despite the lurt:wn etlicacy of radiation t]rerapy iu the sening of locally advanced or ruedicall,v
inoperable NSC'LC and the irnprovements in the teclurical aspects of radiatiol therapy delivery
(5). the treatmerrt outcornes leave significant room fcrr intprr:venrent. Median sruwival rates
accr:rcling to randoru.izetl trials are in fhe range of l0-?8 urr:ttlhs. Historicallv. 5-year stnvival
rates are l0-l5oo. Local recturerrce rRtes occru iu 50-709'o of cases (6. 7), artd local lirilures
con'elate r.vith climinished sut"t,ival (I).
The crurent standard of care fr>r locally advauced rnedically inoperable NSCLC is cornbined
mr:clality racliatiou therapv ivith concur:ent platiutuu basecl doublet cheutotlterapv. The
stanclnrd RTOG regimen for r:heurorarliotherapv cottsists of carboplatin (AUC=2) and
paclitaxel {5(} msrmr) troth clelivered weekly with 60 Gy r:rf racliation therapy delivereel rl 2 Gy
daily tractiorrs. These tleatruents are rvell tolerated rvith expet'ted toxicit-v rates of netttlopenia.
deruratiti s. esopha gi tis. pneuutouit is ( about 20o''b-3 00,'o) ^
.1.2.1.1 Rationlle for PD-l Blockatle rvith Ratliation Thernpy
The cornbitatiou of radiation therapy and inuuurrotherap-v is a promisiug nerv treaturent
shategy in solicl hrmr'xs. Radiation therapl'g,eoerates att iuutuure resPonse with the inct'eased
preseutatiou of altigeus r.ia Ir,[HC Class I artd sutrsequent 'I' cell recognition of in"adiated cells
(9). Despite racliariou therapv stinurlation of the iuuuune systeu. an iuumurologic equilibritun
results nherebv huuor attack atter radiation therap-v diminisheg. PD-l blockade etiltances
firrther tuuor destructiou b1' lrruiting the state of auelgy and provides a poterttial springboard
i-or achieving au itnltrovenleul in the t:ue fbr lhese patiettts.
Inhibition of PD-l rual-' pennit irnl:rovetl turnot' rejection. For exarnple, usittg PD-l deficieut
TC'R Tg T cells. the absence of PD- I rvas associatecl rvith urarked iruproved nrrlor rejection in
vir.o. even rvith CTLA-.I deticient T cells did uot reject (10). Liker'vise. polycl,rlal antibody
agaiust PD-Ll car) ptoulote tur)tor rejection in tnrrdels (ll). PD-l is expressed directly ou
trunor cells altl therelbre rnakes il an attlactive targel {br iuutiture-rt
l\t':
t.' L
11,1.i

Protluct: Perttlrroliztuttatr
Protorol/Arneutlment No., I, 
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Contidrntl*l
therefore follows. that PD-l blockade w,ill prornote lrunr:r rejection by limiting inuuune altel'gry
and will penuit irunune-urediated interpretation of a neoplasu as foreign signal rvamattting
attack.
Liang et al clernormtratetl that the differeutial re$ponse of tlutor to RT in ilrcliviclual niice is
con'elated rvith the nragrritude of the T cell respouse to fturor antigens. Ag-specilic T cell
responses r.vere signrrlicantlf increased in the radiatiort group compared rvith the turin'adiated
glor{). T cell respor}ses rvele lorver in auirnalii rvith stable disease. Il rvas torutd tltat atrlative
racliatiorr therapf iucreases the ti'equenc-v* of Ag-specitic CIDS+ T cells that irrtiltrate the ttunor.
but hoth overall T cell iufilttation and cltokine productiorr decrease over tirue in the htrttor
microenr,iroruuert, proclucing raciiatiou-iuduc:ed hunor eqtrilibriurn. This equilibriuru can be
conibatted b-v blocking PD-l usilg a neutralizulg nlltibod-v to release sttppressiott of PD-1+T
cells r.vithin the tuuror uucroeuvironurent to restilt iu tuntor rejectir:tt in the setlirrg of in'adiatecl
nunors (11). \.'ert:r'ugge et al have corloborated similar fincliugs {1-l)^ Tltereti:re radiation
ilrclucerl nulloL ecprilibriurn carr be clisrupted tr: ,vield cornplete reEression of ttntrors using PD-
I blockade.
4.2.1.2 Data Supporting Concurrent Immunother*p-v and PD-I Blockade with
(loncurrent Chemoratliation
Available preclirrical clata about inuututr:therapy collctureut r.vith radiatir-rrr suggest a l:enetjt to
courbiniug iuuururotherapv dunng radiation therap,v. For exaurlrle. Dewan and colleagues
cteuroustrated that tractiouatedracliotherap-y was able to cattse slriukage of trunol's outside of
the racliation tield rvhen combiled during CTLA Lrlockade. Wherr CTLA blockade or radiatiort
tlrernpy wirs usert aloue. then the eft'ects on the priruary and clistinct seconclarY disease
demonstratecl less respouse tharr concutent therapy {14).
Sirnilarly. alrti-PD- l blockarle rvitlr stereotactic radiation is able to produce lottg-lenn sruvival
in ruru'ine glioma ruodels. \\'hen coucrulelt therap,v rvas trecl. the brains of mice harborerl
signiticantly ilrcreased C'D8 effector T cells coniparecl to ntice tlint ttid trot receive radiation.
Theretble. the trlockacle of PD- l allorvecl for synergisru rvith racliotherap,v. Also of irtterest. is
the apparent "cu'e" 
"vith 
PD- l in the experiuental portion of the sttrd.v: rnice tltat sturivecl
ruore than 90 davi; afler cranial RT. and then rvhen re-challenged rvith malignartt cells did not
develop recruleuce. sugeestirru s1'sternic iuunurit-y. Iu contlast. rnice rvitltottt prior expostlre
to PD- I clevelopecl trunor grorvth atler re-clmllerrge ( l -1).
PD-LI expressiou in tlre ftruor microenvironmeut has been associated rvith poor outcotues
alter chernoRT ( l6). Deug et al described that local upregtrlation of the PD-L I iPD- I axis after
RT suppresses iuunune l'espouses. rvhich then linrits the tirll expressiott of atttirtuuor irmutrnity
arrd cnu leacl to relapse. Bv corrrtrining RT ancl PD-LI blockatte. antihuttot'iluururiry'is
optiurzecl aurl leacls to the eliuiuatiou of ruyeloid-cterived suppressor cells via T-cell-derived
T\T. PD-Ll blockade enhauces RT by'alleviatilg the inhitritoty action of PD-LI on t cells
aud treats tht-, prinrary tuurol ax rvell as rnetastatic (hotlr gross and occttlt) disease in distanl
8

Protluc( : Pernlrrolizurtiab
Protocol/Amentlmeut ro.' I,' 
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Gonlidonlial
sites (17). Likervise" in s lrreast cancer uroclel, Treg cell ablatiol with PD-l blockade with
tulnor in'arliation srgniticantll. reduced nurlclr btrrden attd improved overall stuvival courpared
to Treg iuhibitiou alone ( I 8).
Iu brenst cflrcer and melanonla mr:dels stlclied by Shnrabi et al (19). it was forurd tlrat radiation
theral:y incluced euclogeuous antigerr-specit'ic iuuuuue responses rvith cr:urbinecl rvith antiPD-
I checkpnint blockade inununotlrerapy. Iuunune-stiunrlating effects of r-adiation tlteraplr rvere
increased rvlren radiation therapy lvrrs conrbined rvith anli-Pf)-l therap,v. resulting iu the
developurent of auligen-specific T cell arrd B cell-urediatetl inuurure t'espooses. RT increased
the percen(nge of autigeu-experieucecl T cells and etl'ector meuroly T cells. RT also
upregtrlated hrmor-associated antigen-N'fHC complexes, edtanced atttigen ct'oss-pr.eselltatioll
ur the dt'aining l_vruph ncde and increa"sed T-cell intlltratiou itto htmors.
Theretbre. the avnilable preclinical data supports tlte use of concun'ert PD-l blockade with
concrurent RT, as PD-l iuhibitiorr charrges the ftunor ruicroenvirorl[]ent to reduce Treg cell
tiurctiou ancl iurprove the ellicacy of RT. Tlrrs corubinatioll of PD-l inhibition and racliation
therap.v cau prime endogenous antigel-specific inuuuue respollse and plovide an additiorlal
rureclmlistic ralionale lbr courbiuing raclialiotr rvith PD- l blockacle.
4.2.1.3 Clinical Data in Support of Combined PD-l Inhibition, Chemotherapy, and
Rrdi*tion Therlpv for )ion-Small Cell Lung C:rncer
It is apparent that the role of the irrumure svsterlr response is paranrourt in the overall outcoule
lbr the patient. Iu a set of uon-*iurall cell lturg caur:ers (T'{SCILC). CD3 or CD8+ Ttuttor"-
intiltrating lyruphocytes {TIL.r) rvere a"ssociatecl,,vith better outcon}e iu NSCLC {20). Recent
stuclies ilcorporatiug iuuuuuotherapy rvith hurg cBucer ltave deruotxtrated gteat proluise. A
shrdy of Ir{K-3475 monotherap.v tbr previousl-v treated non-suall cell lurg cancer
deurttustrated objective re:jporse lates of 2.1o0 b,v iuuuune-r'elated respon$e cdteria (irRC') aud
2lqb by REC'ISTI.I. IUedian cluratiou oi respouse by irRC was uot leaclted at a ntedian
duratiou of ibllorv-np of 62 rveek.s (?1i. Also. nivoluurab ha"s recertl-y treeu sltr:rvn to lmr.e
single agent activitl.' in sqnarnous cell carciuorrra r:f the ltutg atler rleutotmtratiug a 14.5 orb
objective response rate and rnetliau tiure to resporlse of -1.-1 months r.vith a median dtuation of
respon$e that has nol y.'et treen leaclted (::).
The START trial speciticallv adclressed the que$Iiorl of inumurotlterap-v after
cheuroradiotherap\, usilg a l{tl('l ailtigeu-specific inuuunr-rtherapy (tecenrotide). Also
median overall survir.al rates were not sigtificantly ditferent r.vith tecemodde versus placebo.
ixrt ftrr those rvho receivecl plior concurrett clremoradiotlterap-v. the tnerliart overall suvival
u,as -10.8 morrths rvith atljul'an{ tecelDotide versus 20.6 rnonths fbr those rvlto received adjrrvnrrt
placebo (?3) and susgests a syllergy l.letrveen chemoradiotherapy alrl irruurure modulatiolr. A
,3o"o rate of pneuuoria rvas seen.
PD- I blockacle irt locallr, aclvartcecl
I
Er:alualing ther posxible conrbinatiou <lf clteutot'adiation and I
NSC'LC rs r:f gleat irrrportance giverr the relatively pot-rl trrrl,it'al r"rut

Protluct: Peutbroliautmb
ProtocolJAmentlmeut ao., I, 
,
C 
Conlid{tntirl
ruetastatic disease. and strggestion that racliotherapv rvith PD-1 inhitrition has potential for
s-vnergism. Herein, we pr'opose a trial rnoviug PD- I i:lockade into ctretttoradiation iu a phase
I stucly. giveu the pt'rssible risk olpnettutonitis rvith both therapies.
4.2.2 Rationnle for Dose Selection/Reginren/llodification
Arr open-lal:el Phase I trial (Protocol00lj is being corducted tr: evaltrate the safety aud
cliuical nctivity of single agent L{K-3475. The dose escalation portiorr of this trial evaltrated
three dose levels. I rugiftg. 3 urg,ilig. ancl 10 urgikg. *drninistered everl ? rveeks (Q2W) nt
sutrjects r'*ith adr,anced solid ftutlors. All tlu'ee dose levels rvere rvell tolerated attd tto tlose-
linriturg toxicities rvere obser"ued. This lirst ir lttutran stncly of N"{K-3,17,5 showed eviclettce of
target engagelneut and objectir.e evidence of hunor size reductiou at all dose ler,els ( I urgikg,
3 mg/kg aucl l0 urgikg QIW). No N{TD has been ideutified to date. I0.0 nrgi'kg Q2W. tlre
highest close lested iu PN00l.lvill be the dose ancl scheciule utilized irr Cohorts A. B. C ancl
D of tliis protocol to test ibr irritial trunor actrvity. Recent clata fi'our other clinical rtuclies
rvithin the N.fK-34?5 prr:graur has shorvn that a lower dose of MK-3475 and a less ti'equerlt
schedule uray be sufficieut tbr target engagerneut anrl clinical activitv.
PK clata analvsis of NIK-3475 adrnini.stered Q3W aud Q3W sholvecl slo*'systeuric clearauce.
lirrrited voltuue of clistribtrtion. and a long half-life (reler to IB). Phannacoclyttatttic data (IL-
2 release assa.y) sug.uestecl that peripheral target etlgaqerletlt rs ctu'able (>? I days). This
early.' PK and phamracodytauric clata provit{es scientific rationale for testirrg a Q2\V and
Q3\\i di:sirrg schedule.
A population pharuracokinetic anall'sis has beerr per{irnued using sentut c't"xcentration tuue
data frorn 476 pafieuts. \\:ithiu the resulting population PK model. clearanc'e artd voluure
pitraureters of h.1K-3.175 rvere ftlurd to lre dependent on body rveight. The relation.ship
trelween clearauce arrtl bodl. rve'iglrt. rvith al allouretric exponent of 0.59. is rvithin lhe rattge
observed li-rl other autitroclies anrl rvould support both trodl, rveiglrt nonualizecl dosirtg or a
frxecl dt'rse across all body rveights. il.'tK-34?5 lms been fourtcl to hnve a rvirle therapetrtic
range basetl orr the ruelauonra indicatir-rn. The diftereuces in expo$tue tbr a 200 rrg tixed
dose regirnen relative to a 2 rugjkg Q3W botly weig.ht based regimen are arrticipated to
reurain r.lell tvithin the estatrlished expostre utargirn o[0.5 - 5.0 fbr 1\'{K-3475 iu the
urelauonra irrdicatiou. The exposule margins are basecl on the noticto of similar efficacy aud
safety in urelanorna at l0 nrgr,ikg Q-3\U rs. tlte proposed dose regitttett of 2 nlgr'kg Q3W (i.e.
s-fold higher dose aud exposrue). The popnlation PK er.'trluatiott revealetl that there was no
signiticant iurpact of huuor burdeu ott expostile. In actditiou" exposlue was situilar trefi.veen
tlre NSCLC" and nrelauonra irrdications. Therefot'e. tltere are llo anlicipated changes irr
esposrue behveeu dittlrerrt indication settitlgs.
The rationale lbr'firrther exploration of 2 mg,ftg aud courpat'able doses of perulxolizurunb in
solicl hunors rs based on: I ) similar etticacy and safety of pernbroliaurtab whett dosed at either
t0
rse relationshi
? rrrg.lkg ol l0 rngikg Q3\[I in ntelanonta patierrts. l) the t)at expostrre-t

Product: Peutbroliauttab
Protocol'Atneurllneut to., I,' 
,
C 
Cor'fid$ntial
of perrrbrolizturrab fcrr both efficacy ancl safetv itt the dose lauges of 2 urg,'hg Q3W to l0 mgilig
QjW. 3) ttre lack of effect of tuutor trnrden or irrdicati,tn on distribtttictt behavior of
perntrrolizrunab (as assessecl lry the 1:opulation PK moclel) and 4) tlte assttruption that tlte
d!'rmruics of perubroliztuuab targel engagernent will not var-v rueaningfrrlly with nrmor t1pe.
The choice of the ?00 mg Q3\[' as an appropnate dose tbr the switc,h to tised dosing is Lrased
on simulatiorx perfonued using the populatiot PK utodel of perrr[:rnlizrunab showirtg that the
fised close of 200 rug every, -1 rveeks rvill pr:ovide exposrues that l) are optirually corrsistent
rvith those obtairred rvith the ? ruglkg dose every 3 rveek.s. 2) rvill rnairttain individual patieut
exposlu'es in the esposru'e range establislred irr rnelanoma as associatecl rvith maxirual etlicac-v
reipou*. ancl 3) rvill rrraintain iut{ivicttral patients expc}stue in the exposure t'ange establishect
in melanoma that are lvell tolerated and sate.
A l'rxecl close reginreu rvill sirnplity the dosing regimert to be more conveuienf fbr ph1'sicians
and (o reduce potelltinl tirr closing enors. A fixed closirrg scherue will alsr: redttce cornplexitv
in lhe logistical chaiu at treatulent facilities aucl reduce rvastage.
4.2.3 Rationale for Endpoints
The priurar-v ol'rjective of this trial is to characterize the satett, and tolerability of
pernbrolizuruatr in sul;iects rvith inoperable,llocally aclvattced NSCLC' treated rvith
cheuroradiatir-ru therapv. The priurar-v safe[,'aualysis rvill be basetl ou sttbiects lvho experiettce
toxicities bnsecl ol ('TC'AEv-1.0 criteria. Saiet.1, rvill be assessed by'quarttifoirrg the toxicities
ancl grades experienced by sutr-iects who bave receivecl perubrolizuruab incluclirtg serious
adverse everrls (SAEsi ancl er,euts of clinical iltterest (ECIs).
Safet-v r.vill be assessed b.v reported adverse experiences usiug CTCAEv4.0. The attribution to
dnrg. tiure-of-ouset. drration of the eveut. its resolution and arly concotnitant utedications
adruiuislered rvill be recoldecl. ACs rvill be anal-vzetl includirrg but not linritecl to all AEs.
SAEs. tirtal AEs antl lalrornton,c'hauges. Fruthenur:re, specific itmmure-relatecl adverse events
(irAEs) rvill be collected and clesiguated as in:mrure-relatecl event of clinic interest {EC Is).
.1.2.J.1 Efficacy Endpoints
The priurar-v goal of this hial is to evahmte the satety and tolerabilitl,' of perntrrolizuuraLr in
combinatiou rvith cheuioradiatii:n therapy tor inoperableilocall,v advattcecl NSCLC.
A see.ondal ol1ectir.e is to er,ahmte local nud melnstasis-fi'ee stuvir,al. progressiott-tree ar:lcl
overall srur.ir.al. Overall response rate basecl r:n R-LCiSTl.lrvill be assessed by the
investigators. Subiects tnust have ureasruatrle disease. Respouse rates rvill tre corulrared to
historir,'al resrilts.
ll

Product: Penrbloliztuub
ProtocollArneudment so.: f 
i -i
C 
Con{identlnl
{.2.3.2 Biomarker Resesrch
Sutrjects rvill be required lo have nervly obtained core or^excisioual trtrrtor lriopsies to suppotl
the abiliry to investigate the correlalion trehveen PD-L I proteir expression by
iuuuunohistochemistrl and the anti-turnor activity of pembrolizumab in locally advanced
NSCLC'. If a relatiorrship can L;e ascerlaiued. theri a tlueshold tbr optirnal prediction of
re$ponse can be deteurrined.
Subjects rvill be eru'olled ou tlils tlial regardless of PD-L I e.xpressiou. Thus tissue availabilit.v
but not high biourarker expressiou is reqrdred tbr trial entry. This data will tre of importance
gir.en the uovelty of the corubination of pernbrolizuruab conctuteni rvith cheuiorxdiation.
Subjects rvill also rurdergo evaluation of T cell reiipouses at weeks l, 3. 6 drning
cheruoradiation therapy arrd before each adruinistration of perrrbroliztunab ftrr cycles 1. 2. 3.
Due to the expected inurnure stirmrlation from courbitmtion cltemoradiation therapy and
penibrolizumab. it is likely that this combination will result in increased effector CD8+ Tcells
and decrease in C'D4+FoxP3+ regulatory cells. These levels will be meastued via flow
c-vtontettl*.
4.3 ExploratorvObjective
5.0 METHODOLOGY
5.1 Entry Criteria
5.1.1 Diagnosis/Contlition for Entry into the Trinl
lv{ale/Teurale subjects at least I8 .vears of age with iuoperable nsu-small cell lturg cancer who
are eligible tbr chenroradiatian therapy lvill be erunlled in this trial.
5.1.2 Subject Inclusion Criteria
l. Wrirten infonned cotseut aud HIPA{ authorization for release of personal health
itfbntraliorr
7. Age:'" l8 years at the tirue of couseut
3. Snirjects r.vith any kiud of NSCLC histology docurneuted by histology orc)'tology fi'orn
brorrclial trruslring ol rvashing. or ueedle aspiratiou of a defined lesiorr trut not fi'oru
sputrrur cfr:logy alone.
4. N{ust har.e A.IC'C' 7'h ecl. uropel'able Stnge II disease requiriug clteuroradiatiorr therapy
or stage IIIA or IIIB NSCL(I based ou appropriate slagiug shrdies iucluding brain MRI
or heatl CT. CT C'hest. and FDG-PETICT scau"-
ll
tlii
lr' i t

Product: PetuLirolizttrttab
ProtocolJAtnendment so.: f 
, -i
G Confidsntiel
J. Be willing to provide tissue trour a uewly obtained core or excisional bir:psy of a nuuor
lesiou. Nervl.v-ot:tained is defined as a specirnen obtained up to -3-5 rveeks (250 days)
betore iuitiatiou of treatrnerrt on Da;* l. Subjects ibr whorn nervly-obtained sarnples
caurot be provided (e.g. inaccessible or subject safrry* concent) may subrnit an arclilvecl
specirnen only upou a€{reeruent tiorn the Spr:nsor or may tuidergo Firte needle
aspiration.
6. ECOG pertbnuance status of 0 or I within 14 days before registratiott for protocol
therapy.
7. Adequate laboratory values obtairred within 14 tlays before registration tbr protocol
fherapy.
Table I Adequate Organ Furction Laboratory Valttes
Svrtern
LsLrorstorv V
Hemrtological
Absolurc neutrophil corurt {AN(-)
1.500 :nicl-
Platclctr
" 100.00t) urcl
Hemoglotrirt
l9 gtdl or fi.6 nuuol L rvitlroul fralsftlsion or EPO depcndtncl'
(rvithil ? dayl ofarscrsrnerrtl
Renal
Scnrur crrratininc 0R
Meaqucd r;r calcrdatedt creatiniuc
clcarance
(GfR cal alro be used in plact ol
creatinirie or C rtlll
11.5 X rrpper linrit oirrtrnual ttLN) OR
,:60 nrl:nrirr for rrrtrject rlith cr-Entin.int lclel* :" 1.5 X
in:rinrtiorral LiLN
Hepafic
Seituu rotal hilirrrbur
.j 1.5 X UL\ OR
Direct bilirubin'r Lll-N Ior rrtbjects rvith total bilinrbin levels >
I.5 L'LN
AST {SGOT) end ALT t,sGPT)
r,r'ith liver lneta!I.ries
: 1.5 X ULN 0R
3 5 X ULI{ for rut
Albrurrin
:'1.5 urg cll
( o:rgulatiou
Lrter:ratiotal Nonnalized Ratio {I}iR) or
Plotluonrbin Tinre (PT)
.A.cti"..ated Partial Tluornboplnrtil Tirne
(aPTT)
1l,5 X LL!'l unhsr srrbjtct ir rccciving anticoagulant thcrapy
Rl lolg ar PT or PTT is rvithil theraperrtic range ctf irttcndecl lrsc
oi anticoagulants
51.5 X tll-N urrlesr lubjcct il receivirtg nuricoagulart iheiapy
ar laug a* PT or PTT is u'itbin therapeutit'rartge of intended use
of ;rnticoasttlults
r('reirrinine clenrancc should bc calculater"l per i:r:tinrtional :t.tud.rrd
t3
L Forced expiratorl
blonchoclilators by
yolume .' 1^0 L 01 ;," *Oo.O
pulmoilaryI fituction testing.
of preclictecl lvith t-tr w:thotlt
rlt)
l\ I j

Protluct: Peutbrolinuttab
ProtocolJAmeutlmeut ao.t I',
C 
Contidontial
9. \Vornel qf childbearing poterrtial shoukl have a negative lurle or selnul pre€urancy
r.vrthil ?l horus prior to receiviug the first dose of stud;* me<iication. If the tuirre test
is posilive or carurot tre conlinned as negatirie. a sellutl pregnaucy test will lle required.
10. Wtruren of chilclbearirrg poterrtial should be ruilling tc! ruie ? rrietltods of birtli conhol or
be surgically sterile, or abstail fi'om heterosextml activity for the coluse of the study
tluough l20 da,vs atler the last dose of study medicatiou (Refereuce Section 5.7.7).
Sut:-iects of chilcltrearing potential are lirose lvlto ltave not been surgicaliy sterilized or
have not been tiee tiout urenses tbr :, I year.
It. Nlale subSects shoulcl agree to use an atleqtmte urethod of contraception starting rvith
the tirst dose of shrdy therapy tluough l20 days after the last dose of strrdy therapy.
12. Have measurable clisease based orr RECISf t.l
5.1.3 Subject Exclusion Cr:iterin
L Is crulently pflrticipflting and receiving shrdy therap-v or has participated irr a shrdy of
an investigatii:nal agelt and received study therap-v or used an investigatiorral device
rvithin 4 weeks of the tirst dose of tleatrnent.
2. Has a diagnosis of inunurodeticiency or is receiviug s.vsteuric sternid therapy or ally
other fonu of irunlurosuppressive thelapy' rvithin 7 days before the lir:st dose of trial
treaturent.
3. Has a knorvt history of active TB (Bacillus Tuberculosis)
).
HJlrersensitir,it-v to peurhrolizutuatr or an,v of its excipierrts.
Has had a prior anfi-cancer uonocloual nritibody (ru"{,tr) within 4 weeks prior to shrdy
Day I or rvho has uot recovered (^i.e." "r Grade I or at baseline) fiour adverse events due
to agents administered ruore than 4 rveeks earlier.
Has had prior chemotherapy. ialgeted suall molecule therapy. or radiatiorr therapy
r.vitlrin ? weeks prior to shrr$ Day I or rvlio has uot recovered (i.e.. ": Grade I or at
baseliue) ti'out adverse events chte to a previotxly aclntinistered agent.
- Note: Srrbjects with",': Grade ? netropathy are ail exceptiou lo this criterion artd
uray quality lbr the study.
- Note: If subject received urajor srugelv. they mrnt have recovered adequately
fu'our the toxicity ancilor conrplications liorn the inten'entiou prior to starliug
therapy.
t4
6.

Ploduct: Perttlrt'oliaunab
Protocol/Atneutlmeut \o., I' 
:
C 
Conlidential
Has a llrou'n aclditional rualignancy that is prr:gressing or requires active treatruent'
Exceptious iuclude brisal cell iarciroum of the skiu or squarrolrs cell carcinoma of the
skilr t[at has rurdergone poteutiall,v curative therapy or in sittt cervical carlcer.
Has knt'rrvn active cenffal lter\:ous systelr] (CNS) melastftses andior carciDorr}atotrs
nelilgitis. Subiects with previousl-v treated braiu metastases tuav ttot patlicipate.
Hns actiye auloiuunrne tlisease thal lras reryril'ecl systelilic treatulent in tlte past ? years
(i.e. rvith use of clisease rnr:dityiug ageofs. cor"ticosteroicls or inumurosrtppressive
.lnrgs). Replacerneut therap-v {eg.. tliyroxine. irrsulin. or physiologic cr:rlicosteroid
,"pL."r,*rit therap.v ftrr adreual or pitrritary ilsrdficiettcy, etc.) is not cottsidered a tbnn
of systeuric treatutent.
10. Has a [istory of (uol-infectious) pnetuuouitis thal required steloitls or cturent
pneuurortitis.
I i. Evideuce of interstitial hurg disease.
12. Has au active infectiorr reqtriring systernic therapy.
13. Has a liistory or cument evideuce of auy condition, therapy- r:r laboratory abnomality
that griglrt confoturcl the results of the trial, intertere with the subject's participation for
the ftrll druatiol of the trial. or is not in the best inferest of tlre subject to participate. in
the opinion of the treatiug investigator"
14. Has knor,r,n p.sychiatric or substance abtue disorders that would interfere witli
coopemtion with the requirements of the trial.
15. Is preguaul or breastteeclirrg{. or expectirtg to cottceive or tbther childr"en within the
proieciea dtratir-rn of the rrial. starling with the pre-screeniug or screening r,isit tlu'ough
l?0 tlays atier the last close of trial tleluuent.
16. Has receir,ed prior therapy with an auti-PD-1. arrti-PD-Ll. or auti-PD-LZ agent.
17. Has a lororyg history of Hurrmrr Inurrunodetlciency Vinrs (HI\') (HIlr l/2 antibodies).
18. Has klr:wtt active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e'9.. HCV RNA
[qualitative] is detected).
19. Has received a live vaccine rvithin 30 ciays of plarured star-t r:f shrdy therapy.
20. Pleural efftlsion that carurot be controlled despite appropriate interuentions.
? l. History of allergy or hlperserrsitivity to any coruponeut of the treatment"
l5
1.

Producl: Pelttbtoltztttttab
l'l'ril.rcol -{lJl€l(rttltul -',,-- I 
-'
C ffonfid*ntlai
li. No active $econd cancel's
5.2 Trid Trentments
The treatment to be used iD this trial is outlined belorv in Table 2
Table 2 frial]'teatrneut
Treahlest will coltilue fbr up to 12 urouths" iu the abseuce of prohibitive toxicities or disease
progression.
Trial h.eatrnenf shorilcl begin on the clny nf euollment or as close as possible to the date on
which treanuent is allocatedrassigtred.
5.2.1 Dose Selection/$'Iodificntion
The dose aruorurt required to prepare the Peurbroliztunab in&lsiorr soltltiolt is a fixed dose as
per Table ? of either 100 mg every 3 weeks or 200 mg evely 3 weeks'
5.2.1.1 Dose Selection
Ihe ratiolate tbr selectiog of doses to be used in this trial is provicled in Section 4.0 -
Background ancl Ratiouale.
Details o1 preparatiorr a1rd adrniuistration of pembroliztrnrab (lvfK-3475) are provided in the
Pharrnacy Marttral^
5.2.1.2 Dose Motlificttion
l6
Dnig
Dose:Pottncv
Dose
Frequency
Rorrte of
Aclurinistratiott
Regitue* Treithllelll
Periocl
Llse
Peurtrrolizurrab
?00 mg or
100 tttg
clepeuding
on trial
scheuta in
tuli::ll:1
Q3\\,
IV iufusion
DayIofeachirveek
cycle
Expelitnental
Aclverse e\.,e1ts (6ot| rrol-serious and serious) assr:ciated with perubrolizuntatr erpostrre may
represerll au irrurirntologic eliolclgy. 
'1 fiese arlvet'se evettts may occttr

Protluct: Petubloliauttab
ProtocollAmeutlmeut ao., I, 
:
C f,onfidrnliei
gr seveLal urogths atter the last dose of treatrnent. Perrrbrolizumab mrnt tre rvithheld for dnrg-
relatecl toxicities ancl severe or life-tlu'eatening AEs as per Table 3 belorv. See Section 5.6.1
and Eyeul:i elf Clinical Iuteresl Grriclance Docurueut for strppr:rtive care grridelines. iucluding
use 0f corticr:steroids.
Table 3. f)ose llotlilication :rntl Toxicitr,llrrnugenrent Grritlelines for Inrmune-related
A[s Associated u'ith Pembrolizunrab
1i
Geueral iusfruclious:
1. Corticosreroitl taper s[ogld tre initiated upou AE irupror^ilg to Grade I or less nrxl coutitttte to lapet or"er al lesst I
u'eeks.
Grade I or.0 agtl corticosteroid has lreel tnpered. Penrbrolizrurrilb should be lretruanetttl-v tliscontinuecl if AE does rtot
resolr.e u'irhin I I ri'eekr ol lasr dose or cor-ticosteroiils cnrmot tre reduced to ": 10 nrg prechtiso:le or eqttitaleut per da-v"
u'ithur 1l u'eeks.
J. For seyere ancl life-tlueatertlrg irAEs. IY corlicosteroid slrould be initiated fir:t tbllou'ed by oral rterord. Other
ilruururosup1rle!sive trextlueut shonld [:e iriitinted il irAEt cattttot lre conx'olied b.v* corticosteroidr-
lmrnune-related
AEs
Toxicitl'
grade or
conditious
((:TCAf,r'
-t.0)
Action t:rkeu to
pembrolizurnnb
irAE m*rngernent
rvith corlicosteroid
nud/or o(her therapirs
llonitor nud follorr-up
Pnerunorritir
Grade l
Withhold
Atlnrilister
corticosteroids
(initial dose of 1-f
nrgr'lig predrrisone or
etluivalent) {bllowed
by taper
r 
lvlorriior pafiicipanfs for signi ald
s!lrlptonls oI prtetuuortitis
. 
E','aluale parlictpants u'ith strspectetl
prteturtonitis u'ith radiographic inraging
aud iuitiate cottico,'tet oid treahrent
r 
Adcl prophylaetic arrtibiotics tbr
oppofruristic iufectiour
Grade .i or
.1. or
re!'tu1'erlt
Cirade ?
Pemraneutly,'
discoltiuue
Diaryhea ,'{lolitis
Grade 3 or
-1
\\'rtlihcrld
.{dnrinister
cotticosferoids
{irritial dose of l-3
urgtkg predrlisolre or
eqrrir-aleni) lbllou'ed
tr,v taper
r 
lv{onitor parlicipants for siprns and
$1rilptonrii of elterocolitis tie. dizurliea.
atrdoruinal pain. blood or ll[lctts in stool
g.itlr or g.ii[o1r feverl and of bou,el
pertbratiou (ie. peritorteal signs arlcl
ileus).
r 
Parricipants u'ith ..'Grade ? cliarrlrea
$uspecting. cerlitit sheuld cotrsider GI
consnltalion arrd perlbnnine ertdorcopy
fo nrle out colitir,
r 
Participauts u'ithdiarrhea,'colitis lhorrld
be advised to r{rink liberul quantrties of
clear fluids. If sufficient oral fluitl ilttake
ir not feasitrle. tluid and electroll'tc's
rh.rrrlrlbesulxliluted 
fVjl:lir<in"
Crade {
PennauentlJ'
cliEcoutilnre
t:\
I! 
i
til
I
I
il;rptr;itLrrr Lltle

Product: Petutrroliztlttub
Protocoh'Atnentltneut so., I, 
u
l8
C 
Conridsntirl
ASTl ALT
elevatioll ot
Irrcrtased
trilinrbil
Cirlde l
Glade i or
.l
\\ lltilrLrl(l
r Admilister
carticosteroids
(initinl dose of 0.5- I
Iiler'kg. pfedtrisoue ol
eqrrivaleut) followed
bl" tnper
\'lorritor u'irh liver frulctiou te$ts
(consider weekly or tllore freqrretrtl,v
unril lirer eru)'nle taltre rettmted to
baselile or is stalile
Pennarierrlll'
discontiuue
r Adurilrister
cofii(osteroids
(initial dose of I -1
rugikg pre&risorte or
equivalent) tbllowed
br-. taPer
Type 1 diabetes
rnellitrrs (TIDN{l
ot'
Hyxrglyceruia
Newly'
ansiet
TIDNI ot'
Gracle -l or
4
hyperglyce
rrria
associated
u.itlr
evidence ol
p-cell
farhu"e
\\rithhold
. Ioili&te instrlin
rcplacetuettt therallY
for participalts with
TIDN.l
r Adrninister anti-
hyperBlycernic it
pafiicipiurt"s $'ith
hlperglycernia
Monitor partic ipauts for hypergl.vceruia
or other *igrrs arrd sytllplollls of diabetes
Hlpophl'sitis
Cilacle l
\\'ithhold
r Adnrinister
corticosferoids artd
ilitiate honnotral
replace[rents a$
cliuically indicated.
\{onitor tbr sigrrrs atrd *ynptotus of
irypophysitis (ilchrding hypopindtmism
arrd adreual irrsuffi ciency,l
Cuade -l or
4
Wiliihold or
pellnartelltl-v
discoritinuel
Hyperthl roidisnr
(ira<le l
C'orrlilue
r Treat rvitlt trorr-
seleclive beta-
blockers (eg.
propralolol) or
thionaurider as
aooropriate
. 
Morritor for sigls altd synpfoutr oI
thyroid disorders
Gracle 3 err
4
\\rithhold or
pemianeutly'"
discoutinuel
Hypothyroidisrn
(n'ade 3-J
C'onfiuue
r Initiate thyroid
replaceurett
honrrortes (eg.
lelotltyroxirre or
lioth-vroirrine) per
standard of care
o lv{onitor for sig,rrs atrd spuplorns of
rlryroid clisorderii.
Ne1>luitis zurd
Rerral
dyshurctiorr
(irade l
\\:ithhold
r .{dnlinister
corticosteroids
(precbisone 1-3
ln8:ikg or
equitalent) tbllorved
bv lsper,
t 
Monilor changes of lenal ftulctiou
Grade -1 or
{
Perrnauetrtl-v
dircootir.' re
.-
ilrr:r,i fi*trt

Product: Perttbroliztuttab
Protocolr'Arneudmeut \o. :
S 
contidsntirl
Dosiug iuienrrptious are penuitted in the case of rnedical I sugical events or logistical reasons
not relatecl to sfildy therapy (e.g.. elective surgely. umelated medical events. patient vacatiott.
and;or holidays). Subjects should be placecl back on study therapy within 3 rveeks of the
scheduled intenuption. unless r:therwise discussed rvitb the Sporrsor. The reason fcrr
iutemrption should be rlocuttrented in the palieut's nhrdy recorcl.
3.2.2 Timing of Dose Adnrinistration
Trial treatruent slrr:uld be adurinistered on Da-v I of each cycle atler all procedures,'assessrnents
have lreen completecl as detailecl orr the Trial Florv Chart (Section 6.0). Trial treatrnent nray
be aclruinistered up to 3 cla.vs tretbre or afier the scltecluled Dav I of each c1,cle clue to
adniirristrative l'efl s0rls.
All trial treatulerts will [:e adruinistered on an outpatient basis.
l9
l'11'ocarditis
Grade I or
?
\\rrthlrt.rkl
r Based on ser,eriry* ol
AE adnrinister
cofiicosteroids
r 
Errsrue adeqrrate elahntior to confinu
etiology alcl'or exclrrde other causes
(lr.a<le 3 or
4
Penlarrently
discoutiuue
All other
irurnune-relatetl
AE*
Intolerable,
persistent
Gracle ?
\\rrthholcl
Bared on t1'pe and
seterit-v of AE
adurinisler
corlicosteloitls
Ensrue acleqrrnte evalrratiort to coniurtr
etrology aud,or esclude sther cet$es
Gratle -l
\Vitl{rold or
cliscontir*re
based ou the rype
ofer,eli, Evetls
thal reqrdre
disconlinrmtion
include aud nol
lirnited to:
Ciullain-Ban'e
S-vrrdrorne.
eneephalitis
Grade -{ or
l'eclul'ellt
Grade i
Pen:rraneutly
disconiirrue
1. 'f/ithhold or penualently discorrfiuue peurbrolizrurlab is at the discretion of the itvestigalor or treatittg physiciatr.
NOTE:
For parriciparrrs rvifh Grade -] or 4 irurxure-related endocrinoparhy rvhere rvirldrold of perrrbrolizrunab is required.
perrrbrolinunab nray be resturred s-hen AE resolves to: Grade 2 antl is controlled u'ith ltor:rroual replacettrelf therapy or
achieted rnetabolic corrtrol (in case of T I DI'l).
l!rr

Plotluct: Petttbrolizttntab
ProtocollAmendmeut ao., I',
C 
Conlidnntial
Perubrolizrunab 100 ul.g clr 200 mg will be administered as a -30 mimrte fV inftisiou every 3
rveeks as per trial <lesign. Sites slrr:uld make everv- effr:rl to target iltirsiou tirui[g to be as
close to 30 urinules as possible. Fl*lver.er. giverr the var:iability of infilsion pumpsi frorrr sile lo
siie, a winclorv of -5 rniuutes ant{ +10 urimrtes is penrritted (i.e.. inhlsiorr tiilre is 30 mintttes: -
5 miu/+10 urin),
Tle ptramracy lr{augal coltains specitic iustnrctious for the preparatiott of the peurbrolizrunatr
inftlsion tluid nnd adrniuistratiou of- irtfusiott solutiott.
5.2.3 Trial BlintlingA'Irsking
TSis is at open-label triall therelbre. the Sponsr:rr, investigator and subject will know the
treatureut adurirtister:erl.
5-3 TreatmentAllocntion
A schema to evallate the satery.. of adurinistering pemtrrolizumab with chemr:radiation (CRT)
is providecl trelorv. Successive regimerrs have progressively lottger conctrn'enl trealmettt tirttes
goilg trc,ru post racliatic'rn. tr: 3 weeks overlap, to 6 rveek overlap if tolerated or-irtcrease N{K-
j+:if'oro 100lrg Q -1 \\ryEKS to 200 urg Q 3 WEEKS. The sat'ety is evaluated tlrrough dose
lirniting tr-rxiciry* iOf-f) cousisting of gracle .1 pnerunorritis. The 3+3 desigrr rvith dose de-
escalation aud itartilg at Regirnen I rvill be used to find the uraxiurtuu tolerated dr:se (MTD)
regirleu. Atier I\,ITD is founcl. six more patients rvill be treated at h'ITD dose regirnen for a
better evaltmtiorr of the safbty of the closing scheclule lbr tirfiher study. The cletails of the 3+3
design rryith dose de-escalation are shorvn below.
Day 0 is the starl tla-v for cheux:radiation (CRTi
Da-v "tr2 is tlte lrresurned last da.v of cltertroradiation
Table -tr: Tlral Design
START of
PET.{BROLIZU\IAts
D")' of 
startirtg
peurLrroliztutral:
Pembrolizttmal:
Dose
Regirnen
2-6 WEEKS AFTER
C:RT
Da1'56-8.1
100 utg
3'*:5u
?00 mg
Q3WEEKS
-l
2.6 WEEKS ATTER
CRT
Da1'56-8:l
20
I

Product: Pettttirolinlrttab
Pl'otocoliAmentlrntut .o., I 
'a
C 
Confidsntial
A 3-week Dose Lirniting Tosicirr*'period will be observed after each dose level is completed'
zurd before sttbjects are,-eruolled to tlte tte$ dose level.
With starring tlose regiurel l. eloups of 3 patients rvill be entered at a dose level:
o If all 3 patierrts tleated at the dose reginren do uot have a dose limiting toxicity
(DLT). theu the dose will be esr.alated to the rtext close regtrtten.
o if [,'-3 patients fuave DLT. then 3 urore patieuts will be treated at this dose level. If
uone of these arklitional patients has DLT. then the dose rvill be escalated. othetwise
tluee urore pfltiellts are treated at the prior close regirnen (if at ntost 3 patieufs r.vere
prer.iotmly tleated ilt tltat prior dose regirrrerr)-
r If at leasl 2i3 patierrts hnve DLT. then tlu"ee utore patiettts are trcatetl at the prior dose
regimen (if at urost 3 patients rvere previously treated at thal prior dose regirnert).
The MTD is tfie rlose regimeu that 0,16 (or0i3 if at dose level *l) or 116 patiertt expet'iettce
DLTI and at lea.st 2r-1 or 116 patieuts lreated rvith the uext irigher dose regiruelrl will lrave had
DLT,
N6te: If rhe escalatron occrus at fhe last close regiuten {Reguuen 5). tiren the }v{TD is at or
above the last tlose regimen. If the cle-escalatioll occurs at dose regimen -l (at least 2 out of 3
patients or at least 2 out of 6 patieuts have DLT nt dose regirnen -l), then the hITD is below
ihe ck:se regiruerr -1. In either case. the MTD is not detenuinecl ti'orn the trial. But tirr the
fonner. the last regiruen (Regiureu 5) is sat'e and still can tre u"sed safely tbr fiuther stttdies.
:l
: \\,,EEKS BETORE
END OF CRT
Da1'18
100 mg
Q3\\TEKS
1
2 WEEKS BEFORE
END OF CRT
AT START OT'CRT
Day ?S
Day 0
200 ttig
Q3WEEKS
100 utg
Q3WEEKS
-)
4
Af starl of C'RT
Drt"l- 0
200 utg
Q3WEEKS
5

Producf : Penrlrlolizrunatr
Pt'otocol/Ameutlrneut so.: f 
, -i
C 
Confidr*ntlnl
5.4 Stratification
No stratification will occu iu this trial.
5.5 concomitnnt l.'Ietlications/v*ccinations (allorved & prohibited)
Medications or vaccinatious specifically prohibited irr tlre exclusion criteria ale not alloweri
dtuiug the ongoiug tr"ial. If tlrere is a clinical indication for oue of these or other rnedicatiorrs
or vacciuatiots specifictlly prohibited during the tr"ial. diseontirruation from trial therapy or
vaccinatiott uray lre required. The investigator shoultl discuss any questions regardiug this
rvitlr the lvlerck Cliuical teau. The final decision on ally supportive therapy or vaccinatiorr
rests \+'ith tlre investigator and,'or the subject's prirnary physician.
5.5.1 Acceptable Conconritant I'Iedications
All treatments tlrat the iuvestigator considers nece$sar1, for a sul:ject's rvelfare rnay be
a<lniiuistered at the discretion of the ilvestigator iu keeping ivith tlie couunurity standards of
medical cate. All coucoruitant uredir-'aliorr rvill be recorcled ou the ca$e repo( for:n (CRF)
irrcluding all prescriptiou. overfhe-corulter (OTC). herbal supplemeuts. aud IV ueclrcaiions
and fluids. If changes occtu duriug the trial period. docuueutatiou of dnrg dosage. Aequeney.
route. aud date may also be iucludecl orr the C'RF.
All cottcotuitant utedicatious received rvithiu ?8 days trefore the firsf dose of hial treatruent
and 30 days atier the last dose of trial treatruent should be recorded. Concouiltaut nredications
aduinistered after 30 days after tlie last dose of trial treatnent should tre recorded tbr SAEs
arid ECI.s as defiued iu Sectiou 7.3.
5.5.1.I Radiation Therupv Administrstion
The trse of irnage suidecl ladiation therapf is highly encotuagecl bnt not requirecl.
Radiation and C'hemotlrerapy mmt both begin cu day l.
5.5.1.2 Rlrtiation Dose Specifications
The tetal dose rvill tre 60 Gy iu 30 t'actirins of 2 Gy. Radiatiou treatrnent lvill be
adnriuistered 5 da1,s per week. I fi'action per day. It is reconunended tlrat radiation treatuent
lregin on a lv{onday or Tues<lav. There are no field reductions. All tields unrst be treated daily
artd tlte eutire Pr\'tnust be treatecl clail-"-. Radiation tlrerapy (Rf) corruneuces oll tlay I of
chemotherapy.
Ihe treatmettt plau rvill be nornalized such that 950.,b of the PTV is covered by the
prescliptiort dose. No utot'e thal0.03 cc of the PT\.'rna-v receir,e :, l20o,b of the prescriptiorr
dose (rnaxiuruur dose corrslr'aiut).
21.

Pt'oduct: Penrlilohzrunab
PlotocolJArnentlmeut ao., I 
':
C 
Gonlidentinl
5.5.1.3 Tcchnic*l Factors/Treatment Planning
Beam Etergy: 6 - l5 lvt\,'will be used. Multi-leaf collimation ([.{LC) or individually-shaped
divergent custortr blocks will lie used to spare norrral tissues outside of the target volurne. 3D
Contbmral Racliation Tlterapy (3D*CRT) or Irrtensirl''-N{r:dulated Radiation Therapl, (IN{RT):
Tlre PTV is fo be treated rvitlt auy corubination of coplarar or llcnlcoplanar'fields optiurized
to defiver tlte specil-red dose ivhile restricting the dose to the nonual tissues. Each field is to
be trcated dailv tlu'onshout the corrse of treaturent. All radiation doses rvill be calculatecl
wtth heterogeneiry con'ectir:ns thal take into nccorurt tlie derrsity differeuces within the
inadiated volmue.
5.5.1..1 Localization, Simuhtion, and Immobilization
Irrurrt-rbilization to assure reproclucibility of the sehrp is necessary. Each patient rvill be
positioned iu an inuuolrilizatrou der,ice rn the treatrnent pclsition or a tlat table. A vohuuetric
tt'eatrnent plaruing CT study rvill be required to detine gross turuor vohurre (GTV). intemal
lat'set voltune (ITY), clinical tarsel volurue (CT\i), aud plaruriug target vohune (PTV)(see
definitiots belotv). C'ontisuous CT slices. having no mole than 3 rrun thickness tlu^ough ihe
rcgious harboriug gross ttunor and grossl-v errlargetl lymph uodes and rro rrrore than l0 nun
thickness of the renrainiug regions are to be obtained starling tiour the level of the cricoid
cartilage and extending iuttriorl,v tluough the eutire liver vohune. The GT\', CT\,','IT\', and
PTV aucl nor:ual orgarls rvill be outliuecl on all appropriate CT slices. hrtmvenous (i.l'.)
contlast dru'irrg the plaruriug C"T is optional prr:r,idecl a cliagrrostic chest CIT was cl:ne rvitlr
colltrast to delineate the malor blood vessels. If uot. I\i contrast -qhould be given chrring the
plaruriug C'T.
5.5.f.5 .1-D CT planning
The use r:f four-diurensional radiatiou lreatruent plaruring is highly eucouraged. Acceptatrle
tuethods of accouuting lirr hrmor urotion rnclude: desigu of the PTV to cover the excru'sir:n of
the priruan rind iuvolved nodal CT\: dtrring fi'ee breathing (urotion inclusive). or the nrore
liurited excursion dru'ing e \'ohultary eu autr"ruralir: lrleafh-hold (e.g.. Elekta ABC clevice) or a
gating approach (e.g.. \'ariau RPN,{ s-vstern).
5.5. 1.6 Trrget \,'olumes/N'Iotion l{rnagement Ta rget Volumes
I Detinitiou of the GT\.i: I'he prirrrar-r* truuor iurd clinicalli positive lyrnph nndes seen either
on the pretreatrnent or tlte plaruring CT (:" I crrr shoil axis diaruetel) or pretreatrneut PET
scatt (utaxirnurrr SIJ\' :, 3 ) \irill coustitrrte tlre GTY. Pnthr:logicalll.' involr.ed nodes not
uteeting radiographic criteria also should tre ilcluded il the GTV. The volune(s) ruay be
disjointed. hr the errertt of a collapsed lobe ol lung segrneut. the use of PET 1o distinguish
turilor fi-our tluid,'atelec tasis is euconra getl.
23

Ploduct: Perrrbrnliaunab
ProtocollArnendrnrut so., J.. 
:
t 
Conlldential
* Definitiorl of the C'T\': The C'TV is dellned to be the GTV plus n 0.5 crn to I cur umrgiu as
appropriale to accorult for nicroscopic tuurtx exterxion. Hower.er'. the CTV should rlol cross
nafttral anatr:uric lrarriers to turnor extension such as fissures or thscial planes rmless these
strncture$ are directly abutted or ilvadecl by the GTV. Elective treatment r:f the ruediastiururr
aud su1>raclavicular tbssae rvill rrot be done.
I Deliuition of the PT\r: The intenral tarsel vohuue (ITV) is defined to be the CTV plts an
intemal ruatgin (IIl{) to accorult tbr targetr'organ urotion. The final PTV is detined to be the
ITV plus a setup ruargiu {SN{) to accourrt tbr patierrt positioniug rurcertaintl'ancl urachine
tolerance. These urargins are detenuined as descritred belorv.
5.5.f .7 Criticnl Structurrs
Nonual lissue corrstraints shall [:e prioritizetl in the follow'ing tirder lbr tleafuueut plaruring:
l=sprnal cord. l:hurgs. 3=esophagus" 'l=brachial plexus. atrd 5:hear1.
Spinal Cord: I'he spiual cold iihoulcl be contoruecl ba.sed ou the bon-v liurits of the spiual
canal ti'om the top of C I to the bottom of L2. The spiual cord dose liruit is the highest
prioriq. dose constrnint nnd thus rmrst tre uet irrespective of other cr-lnsn'aints. No more tharr
0.03 cc of the spirral cord nra.v receive greater thau 50.5 Gy total dose.
Lungs: The total hmg voluure is detined as the sum of the volurne of both lungs urimrs the
GTV. The dose-voluure corrsllaint to the hurgs is the second highest priority aud uurst be
uret, except ii it contlicts lvith the cord close constlaiuts. The proportion of total hurs vc,ltuue
that receives urore than l0 Gv (V20) slu:uld not exceed 3lo,'o. Additiorrally, the urean luug
dose shoultl uot exceed 20 G_v.
If either of these constrajnts is exceeded. for the 3D-CRT cases. one ruight iucrease the
weiglrting of auv APiPA tiekls and recluce any clblique tields. fhis can be done as k:ng as {re
cord close (above). which takes precedence. is not exceeded. For 3D-CRT or IMRT cases.
one can reduce the CTY to the minirmurr range suggestecl above especially neal the spural
cord.
Esophngus: The esophagus coutoru should inclu<le llre mucosal. xubruucosa. ar:d all
utnscular layels out lo the tattv advenlitia, h'om the Lro{torn olthe cricoid carlilage to the
gfistroesophageal juuctiou. ]t{o rnore fhan 0.0-1 cc of the esophagru ruav receive :. 6-l Gy. The
rutean dose to the esophngus should be:34 Gy. The esophagrx should uot be
circtnuierentiallf irradiated rvirh :." 60 Gy (i.e.. the 60 Gy isodose line shotrld not eucompass
the eutire axial cross-section of the esophagus at flil-v level)
Brachinl Plexus: The ipsilateml tirachial plexus shr:uld be conloulecl fcrr upper lobe tunc'rrs.
No ruore tharr 0.03 cc ol the lrrachial plexus may receive > 63 Gy.
Heart: The lreart anrl pericardiruu should be contotuecl together fiom the trase to the apex of
the hear1. The lbllowing lirnits ale l'ecorluuended: \,'60 to *;1,'3, V45 to <213. and V40 to
.:l00gi) of the heart.
:4

eql Jo leAal arli m3q ful11uls pemelqg oq 0l a.Iu ssemr1Jlllt rml t lluql aioIII otl E{ltlutl 'saf,Ils
IJ snonflluo) '(r\J.il aulnloA 1361818umtruld pilu '(,tt'll atffirJOA 1af'tut IulNIli)
.l-,\ID) ar*loA.ro..nu *toif *ry.p ol trol}Bllltuls 6tr'ntp pa'unba'l aq llll.r ('rta 'a}Inap JflY
qlr,r .plorl-rlrea,rr] '61y ' i ,) .t; :atirmrulcl t*uito''tt lrt;l;acls-anlxmllet luattra$utrutll nolloul Y
'pa:rnba.r 13 Stnrnruld ;uauqua:1;o ed& aterldo'tt{du aql pru artbttqral
luatrrafurruru rrprlour arll alilltualaP ol sluallutt 11u tlt-r paturcr3'rad aq lsl[tl ]{Ialltssassu uol]oF{
uoIluFrmlS
uorl$zlllqoutul'uoprlnuls I I'I'S'S
.i(lutsrpprru..lllu.ratulspla$aqladuq$ol.a]utlclordt{use.s.tolusuarkuor
.o,fruu Jir,Ui"Au iolctura ,iu," r,iiunq ftrnmuts pttu 6ttua1lur. t:;;f,:tJJ,:r:
rllllrrxutll aql ol luetutsrrtpu au11 a:{ulu ol pasn aq '(uttt sJaUltls a8uug 'afs:a;rol
r"tror rpuroid ,{lalurrbap' o1 q$"on' qr* tq plnoqs sat6:aua tto-,o'td patrales o
.muaq Sunnrucs Eursu .ro sur:lo.tt{ palalluJs ;(la.lrssud 6rusn pa're'tllap aq (utu {ctutaql u0}o'1d -
ri.Iolf,u{ ltllluq)el 0I'I'S'S
asop uoudllrsa'rd aql
.asr:p uorgelr.ltsalcl e{l} iq pa.taAo) aq lsllln (,'11J palurorko:rtn-ttotlotn) tll a{llJtl0''o001 -
..*op p"q,,,,,.,.I.qtJo o.,60f,I paalxa pIIroqS Ald apls{Il 3] 80,0 uBqt a.IoIII()II.l0 3tIIIrIo,l Y _
asop u.t1crt,,,",,i,r, 'r,i*,.i16 
arlLlo %sfJH,:,T;H:ffi,ililli':li:lillltlrX-:S;
Eunl .}s;Soloruo uollBlptlr 3u11uer1rql iq olrlrtloitltlB pe(uasp se (s,116'sAII'AI))
sulBruur roJ ,pB[u nq ,ru, saslruordruo) puB suuE.to IatuJOu ol ta]u$'rolol e'ralq'u ol las
eqplnoqs&uolrdrrro*,"1o1-asopBullalqlr'$lnrq;IpJI'se'IqJnJlslB{uJorIlBJrllrtllr
Jo sfIuII eu,lo,r-esop ,,t'n"Jol Aurp'""' 1ttoq1t* (Eg'd) dO Og aq III'[\ asop 1:aqt'rlsald
Iulol aql .sgoloqcl ^rof, I prru sur:1o1cl.IDJ I'l aq Ill,\A pasrl agu 'tloll,f,u'g racl (1gg) i5
I Emsrr':laarrrlail s.lup i sluaullua.rl eAtaoa^I IIIA\ strLIB ttolorld puu uolo'rcl 
TffaTr__j':*;
suollBrgtrrd5 asog 6' I'$'$
'l'l = StlX' EgU x i9 asop ttolcud = (ag1)
,tg 1 aJar1,n .(aru .sserra,\rlJaf,la lucrsolorq a;\IfBlaJ) d9 ut pal.roda.t aq IIIAI ssop IIolo'Id
.uolslf,ap rolr8qsa:lur ratl su papflurad ,q il!.$ dtlu-r:q1 uof otld Jo tu$o8 uoloJd J0 tsi]
,(duaq 1 tuxeg uolord 8'I'g'S
:'0,{ f ilaupIIJUIYilo]o]o.Id
qulilluII{).IqIIItd :l Jnp0.Id
tr
lsllusFlltlo, s
fl\l
;i {1

'1-Igeq 'srr$urldosa arp su rlsns 'sil?i.ro pe,\Jorrmnt olm iuq:rralxa ilto{J}r,r
(nnu 91,,11D=,\1)) JotInU aqlJo {uorsua}xa ol.'rrrr.ro; Urts'"ruru rrI{rr-g cr: suld AID aql
sl,\J_.) a{lJ -,\J_5r eq} plnlo.tu }IIarraAIo.\ITr lu)rrrrli}qns aql sr arrn}lo..r la6.rut lurrrrrlJ :.\Il -
(,no1at1aas-struf,s pJorl rpuaJq I uo sr\Jl) a(JlJo rro[ilt arl]
sl A.t1;l 'pa$n sI artbrml;a1 plorl-qiua,rq e lJ) 'sellssrl iyrsuap lrrnl reerr .rerlto nro.q Af 11 atlrl
eql qsrrritrrlslp Jallaq iuul luql satprrlii IB)nIII).tatJlo prru I3d rro pasutl.ftr:ssaJau paluiap su
paurporu aq c,slts {utlr r11gr arLL '(,\lCI arueq) AIC eqlJo rror]ourJC] tuetxa aql ssudrrolua
ol 'LtessscallfI 'psl1lpotu ptn slJ polula.iloc .,Lrolu"rrdsa.r arl).tro rlcua uo ,u p e{l;o norllsod
IsUrB eql qll.lA pa:udrnor aq III.r\ AJCI peluarllop aq1 'saiuurl (dII.,'{) rrorlcalrud d$sua]ur
[IntrIIxu[I uo {1tla.rp pa:noluoo errtrlloA.rorrrnl sso.d arp "ro'seiunn pJ]r]Ja.Lroo,,iro1audsa.r
JItt tIo s.,\fD a{ll lo IIoIul} eq}sl tlJlrlAruorlour .rourru .rlr.; rud.ruru sulcl .119 :.\JDl I
'setpus Sttt8utul.Iaqlo pttu l1d uo pasuq,trussararr pauraap su perlrporrr prru 'JJ Sunnruld
asuqc{ al8ms aqt IIo peluJtsuotuep $u as*aslp sso.rd ulrorn{ Ilu sr eunrloA.roulrq sso.rp :AIO r
rorlmrleq 1a8"ru1
uoprau!la6 iuotruuy IBurJo1{ pur'uoqraullsq leAJsI'suollrugag IaBJBI ZI'f'S'S
1",)-Ot roJ S'l'('c rronl;S aaq 'ddu.latll uruaq uolo.rcl
.Iol pluplnJls JtsIlollulllsut atp rad su pa,{oldura aq I[r^\ lnamafcrmlr rrorlorrr ro; saubnqml
'palui,'rprrr su pesll aq iutrr (smoluot
IB{LIe}xe .s}uat}ud o1 6nruuo3ur:a) s.trolpr{ prfr.r a8.ru1prR} saprs g rro lnallud eq} punorms
luql sawB.{i Jui}u}oa.ra}S '6uq-cu,r ro alpu.r}-er6l1u uu Eusn dmpnl}m 'pesn aq duur arqre.rd
ro p"ltlpnuls sllorlnlllsllr finyudrrrpccl aqt of pazlrnolslls nualsls rrorluzrlrqorilurrJo iftaru,r y
'slrrarulua.rl Snr.rrrp lilarflarom pafioilrrof,rxl
ltta,ra:d ot sB os paplo,ru aq pplotls ]uatlud arp .roJ elqul"rolrrrormr srrorlrsod uorlrsocl 1a8.lu1 ary
3() {qtqtiltpoJdar elumaJu Stn,trr:I1u.1o alqedur uorlrsod alquls B ur pauorlrsod aq IIr/r\ sluerlBd
tlor]BZrlrqoIInr{
'sasottntd fnrrnruld ro1 uuJs lsB"rluor-uorr u ol po.retsla-ar at1 l$rmr upis lsu.rlrroJ
a{lt .Io {BppI.I-.I0:\o aq p[notls $ar}Isuap aql 'pasn sI tsurlllor J1 '1; Srrrrnruld aqt Sumq> ua,rd
eq plnoqs lsB.Iluoi snouartB.Illll 'lotlJI 'slassar poolq.rQlcur aqt atuaulJap 0] ]$u.I}rroJ rllrAt auop
sD/\{ I) 1sat1c et;soud'ulp u papljlord luttotldo st 1; Eurmn:1d ary Stnnrp lsB.rtuoJ sllouaAB.t}r{
'uolluprulls.I$J pasn aq IIBrls uorlnrg rrors.ralrror i-IH 's^ (aSf$ ra.uod Emdclols
.IBaIIII alllula.l ttolo.td atruudorddu oIIl qlr,rl sluafiqua.rl uolr"r.rcl JoJ paluJqrlui] lrurr JamttJs I) v
.JIO.lnD sr surcaq
)uamlua.u aqlJo qlud aq;8uo1e.{tuo.laurl s,}ueqed aq1-1o auoil }uql os r16rr:ua a8lul aq lsuur
,ir13l:1lo PIe$ aqJ 'allnlloA.Isrtt[ oJIfIIa atlt qBrro.np dllrxtalut finpua]xa prru a6u1lUuf, prt)]uf,
'0\ lrr JurlluJurY/lo)olo.rd
rlBrrrlrzrJoJqirDd :f Jnpo.rd
9i
l.rllusplruo) $
tf'

{l\(li
lr\Olaq elqul atll
'sullis al8qxa Puu eluIFII In pslBatnlap
s.rnollro; r\In sIIl Eurtltqtuo::r iq paluan aq plooqs AIsl eql 'io -etl0p sI uoll8lllrtls I)
Of uarlAt rr** 
(ailrf) uotl;afold "fitstra1u ttnlullxutr aql uo Pa'mo]uof, aq plnoqs AJSI :
'as8aslpIBpo{Iaq}al8alnlapo}pastlsqpIn0tIS.\&()ptllrl\ausslluosrado.td
puu .uruiqcua:ecl6un1 srll tn rrortua{Illep t.f.rot Jol Pasn aq plllotri ^\opul\r 
8rm1 'rado'rd aq1
'fimnruycl luat(IlBaJl P{Iu IIoI}ualrlap taf.rut.loJ pasll aq lllA\ saiutttt II8)s f-.) ttollulftullsj aILL -.
uorttsalilla6l 1aEru1 €I' I'S'S
'sutxoqtl pttu sttolo.rd qloq 'IoJ nol|uillur\a ttultl
.IO,I
puu f[nmu1d uoloqri 0] lrl?Aala.r sr '"Iatmcttl sttll III Pangi]p 'Atd atJl 'tld aq] alumua8 oNflIII
EE iq {11urrtln.qos, p*puod** il 
^1, 
aql 'stuam}tsor} g.o,t{}ot16rqas rI s{Iollt}I'ru'r Btttptllcttl
.,(le*l1ap lilarqBalJ rr suorlurJu^.ro3 *xrrtotru rrrf.luttt sqJ. '.\II aqt ol pera'\qap illuQru
sr asop paqnrsarcl aql lutll a.IlsIIa ol rrtB.lurrt u srrltl r\I sl 3{IIlUo'\ 1a6'r8t Srnmrc16 :r\Id :
'prtlptlul$ artlruld
Ierr1nln l11a.LnIO Atttlru,ralr{ oqt ot $urp"roocu 'tstEol6}tto uollslpu't 6ut]ea:l:q} '{q 'iruoluuu
i.rri"iiua *l grnprocos palrya puu pa,t\al\e.r aq II*r armrlo.\ sq1 'sasuqd.(lolu.ttdsal lu ttt
s,\L) 11u furtrrquror,{q (g) r(} :aroq.Io'}.IusI['strfuqdosa aql sB t1:rtts 'suu8'to paA]oAulml OltI
furpualxa lnoqtrA\ asuasrp crclo.rso.rrnu lts.,mll3qlls apnlJul 0l lIIIu s {q j\lDI aIIl SmpuBdxe
iq (f t :sdu,tr onr)lo aui) ul paleal: aq '{prtaluunlra-duut i.1I '1111 ,.rI) ItmI g snld ''\-i-C!
.ro'riorlo.., snld ,g3 aqlJo {Ioltnl aq} sl aunllo,r }aElu} le{uatul unu3+.\Igl:.'\J-I :AJI :
n
!lGl!FF!!lF.tt1
IllBa Iu pa.nlt)ln0l
sr\IC II0IIIIl
(qooq
-0F 'ii a) sasuq{i u{)
-urBaq aql JC, $AY
-stas ulup nnmutut
0l ) rrurs Cf I 'trurx
6mqtua:t1aary 1
dmlsa
a'uqluarq aa.q tlllA\
uotll:llltllls 1) C-r
(sgas utup Etudurut
61) nurx (lt I 'Iltirs
Eurqtualq aal; 1
futqlualtl ee.q qlllr
u0tlulnulls f) Q-t'
luaruaEuurtrq
uolfolt
j\Id={IruIS+.\II
,111=(uuug
-s) AJ"J+ttol
'j\I9I=tt0Ilour
JOllnu
snlcl rotrrnl ssor6
alu.raua$ oI Pa$ll
sasuqd IIUJo sA-I.S
aqlJ0 uolml.I0 dI!\
rasutlrl IItsJo CAY
palBJrur;
iq 0l aJE SJnOluo]
orunlor ya8ruS lq1
rlltq.tr uor; saErtul
u0llslnf,lEf, Jsop
JoJ pasn aq ol un)t
suu)s
lsll&t{rplluox c
i.. I 
;'o\ tnrulPnrmYlloJolo'Id
quttnIzIIo.IqIII]d :f JIlpo'ld
lll 0aIII)a(15 su s0l.tutr<

r{}t
'sauuuualun dtl las puu e;(Iu.llo asu] alll u irIIrcd$
anSSIl lUt11lOIl p{IB aiiu.Iar\63 laii.rcl pa1;Irads a'nlstla }stltil palf,a{as s'lalarlu'Iud rtl} 'raAalrotl
:elqulcla)JB sI .Ietllouu ol .oIllUIlsIII auo uI()'{ s'Iela{IIuJBd ase{ll uI saptr}nISBtlIJ0 IIolfBIJu;\
'a)r|lB.rd prr8 srrlslralf,u.t8lls ellnputlr lBlol eql 'IoJ pa$$io:n aq i:tl:::11"l.1,9,9:,*a'{o}'q)
-aulll{rlroJ peqsrlqud rro pasuq Pel,Itl;lse aq iisul -slllpu'' dru:uauts aq} p{Iu {II6'It:rI {}olq
,s'rd.rwr lururxoirl pir' IuI$;p surprrlrur 's.rele11ru.ruc{ iurrnruld }ua{n}ue.rl a{p ell('^$ :,loN :
'-raqli.)llu ol llollUrUIs ll]i]nlllf,
eug 11r0.II dltuucqrudrs;ttus:(ettr 11 '.,uuoleuu s.luatlud puu lottlsuadnror 1 allqJede llaa/r\]aq
a)uBlsrp aql pu8 i6.raua uoloJdJO UOI}f,IIIU U sr u'rqrt[rtra(l tuuaq IIO]oJd ]t]ll] aloN'pasll Etusq
r{ruaq rrolo.r<{ aq} ot ,,,;,J; urqruriuail aqt"uo idtrrprradap paltdlssu aq }sllrl tr8'I*rn l)olq Y --
'slocls 1oq erlrpe.I ol psllloorls ar1 ieut lolusttadruor aq1
(tOOZs.rai(r:rtrrtr)uotlruqsutfulledtrtlruclq:rualu,paqsllqBlsasuullrroiluarllSrusttpalulll)lu)
eq II.^\ slrpl?r irn1uaurs a11l 'paluet,r, *, ,o1nr,raaino.-,t itil 'Iurolurtu eql PrrB tolusuadmor aq1
1o ltrarrnr8llusmr ol enp uorlnql^Ilslp asop uo1ord atll J0 uolltsqmlrad arlt tc4 alusuacltflct$ 0] -
"r*r*r',qriiorrnr,rrl 
a;Arru.r pau*isiu sr sr11i Jo rrolllellor alll Jo aipa lutstp
lsorr erll ,s,111 aldrtlutrr .ro-{ .rm}aq arll lo ,tir*}ra:,urr afttti.r tr. pesuq stttqlttoElu peqsllqulse
' 
fur*,ipirn,irri..,, aq I[,t\ ;\l-l a{} puudxa ol }^{IIErutu lurutxotd ptlu lu}slp atl} 'slxu tuuaq
uolo3d eql 01 lallB.Iud rrorl*.r1p aql fuolt3 'JOAoA\ofl 'suoloqd 'toJ pasrl potllaul at1] ol6ulp'tr:cru
sl AtI e{lt tro.q uolstwclxa lld aq} 'sIxB luuaq riotc'ld a{10} 'lulllrr1:uafuad arruld aqt uI ''\lI
-aqi 
u,o.,: uotstredxa ,g6-"*tuit priu lut prxilrrr us --O 
;;ff?,:t*n ff::T$;?:t|,;T,;
r0l pafir aq illAl srrruaq uolo:rl parrlB)s ^Io (Idsd) .{cluraqt tlo}o'rd para}lBrs d1a'ttssu6 -
suolo-Id - sernpef,ol4 Buruurld SI'I'S'S
's{Iotlnqluslp asoP Bulunlu.La
rol pesn eq oslts iuru sasuqd lrrnPlAlp{il '-IeA;/(oH 'll()[}llnluAe trulcl ptru ufrsap a'rtrpatlu pttu
-lolusuadrno.l .suorlprlilus asop .lo1 pa,iolckua eq IIL{I pastr >^ul]'1s 11u 3o asuresu 'suo1o'ttl Jog
etunrnss3 rfllun} puu Eutuueld lu)lxlu'rl f I'I'l't
8r
.,\1d,={rrui-t+r\Ii
,111=(nrutg
-$) Ar.)+;\rgl
ATCI:
rr8)s plog qlusrq
Il)Ba le pa.nlol[o:)
sAtDJo uorut}
u0Ilelllf,lllil as0p
.r0J tlts)s auo lf,alas
'plctq qlBarq aql
.1o ;trpql:rnPo.rda.r
ssesse
t)l sat{Ill I ul]:]s
pJorl qlca"rq luadag
(.:sv
lll0qll.\l.ro qlun)
ploll IIlsa.Iq qlu\
rr0rlBllrlilIs 1l c-f
Ajd:rmuS+r.\J.l
111=(unug
-g) Ar.)+,'usl
.\IDI=
(o..;gg-gtr id'a)
E0 eq III"I\ muaq aql
rr!!lueptltro) C
', I' 
;i:jHfi,il,1::'l',,,illil1
r1 r..J i
,:1 r."] j

oulsk" aql ul paluaserd sldsilroc aso[Jl rut{\ ^Il]rFtIIuJ aq ltlA:r sJO}uSllsa;ltu }uII.l pa}ladxa sl
U [*r.ira rrql uo slueuuua.rl nolo"rd puu uoloqd qlocl.IoJ parntbal sI 'loo] a.IBAuJos prallnrdtp
agurrn.aiuudo.rddu puu safurur go furlsrsuor '(lUSi) ddu.raqt uCIllulpB.I papnd-adunq :
lurtuluarl paplng aBtrurl lI'I'l't
'a1qu1danetr11
uorlulra( u su parols asu] eql *ulreq pro^u ol 1tuaq eql ulog t(u.,tre slodslotl uounqulslp
nsop irroflr ol paqrpour aq lsrulr srruld luauque.I] 'pa:\al{f,u stl }omlu} elrlt:\ i^Iql uetli11 ****
'anurlllls IB3IIU)
sq] .roJ satrJBA aql ot uortderxa .roJ alqu1 aqi a^oqu lsnl lsq aIIl ttt lallnq lsul sIIl i?g ++*
'a.nu]lul$
IuJrlr.rJ srtll.IoJ serrlul aq] r:l uotlelaf,xa.IoJ alqul aql aAoqu lsn[]sq aq] {fi lellllq lsJI} ees ++
'alqulclarrunn
rrorl?r.\aql ru pagrsrulr aq IIIA\ slrrurl alqutt{ai}iy IIoIluI.Iu.\ a{lt 8rn;aatrt lotl saso(I *
uIJalLI.) aruur ldttroS ptrll sl{ilu.Ilsoo ) a$oq a.Ilu }trl}q I 83I1I.I.)
.alqulrlacrurnl uoriBrlep I pa.raprxror aq IILI\ r\olaq alqef aql fi palsll alqulclarce uollutIuA
Jo slmrrl aqt 8rrpaetxa sasogclats ls.r1; arll aq plnoqs perartlep aq o] asop ttot]dr:rsald
lpg aqt Srr,trollr] prru :.\ld aql rrro,u sa.nucruls rtllp.Itsi aluludas o1 attlrnnpe] .Ietllo{Iu.t,: durtu8
-,{.lotuirelsar '( ,fa) arunlon }a8,rul Emrnruld otll Jo }rud sl a.nq}il}s }Blp.ruf, 1o tlorpod .dttu;1 ;
ip ft su qfrrl su s*lst)p Eut,tlala.I {nqll/rr suiJu
luntrlurdrs rprAt cf, 61 su a;3.ru1su aq IIBI (OU"rt) {C Ot Eur,rtara.t atlltllo.\ at11'atuttpr,t 1aB:t1
,ql io lret{ sr snxalcl lurqJ8lq aq} sJatlrr\ sJo[IrU aq01 rackht Jo .IouIlU sll]Frs :ot.radtts .Io.{ :
aruurlclnlol prolo:clloJ asu) rpua frmror$ JoJ pasn oslu o.Iu {aqt puu 'futrnruld }uatu}Ba.I}
Eur.mp ssa:lo.rd uorluznnrldo arll ftrnuer1srlol.IoJ serulaPlnd su pestt aq uts] sanl8r\ asop
asa{ll '^rolaq alqul aq} m uanrE a,lu sa.fiU)rrns 1u]t]Lt) Iultuotr -totr sltlls,I]slto) illlrtllo.\ aso(J :
SIIII B.IlsUo J sa.IIUJrLIl S lB J IIIJJ 9 I' I'S'S
t I 
:'o,\ tllrutl)nJuYiloJo]o.Id
6?.
%0f .r SF;\
qoig ;0t.\
9'o! [
0,60i " St,\
r og,r
l^ulJH
rr gQ't) ,:" IiJ
.rr t{)'0 j.QtA
**Pr0.) Iulrds
cr !'0; StA
)3 S'0.r; SIA
J) 0'l \ tlj\
r1r 0'[ -" 0l;\
*ssuYaid lBItl)lr.Ig
aJ[a.IaJrmr].II)
lurpudSt: :lr 5'1
; (AffU) iC ft :esop xuI.\l
aJuaJa1{IlrJrtl 1ut1.tud 3o m 1
; (Ig"U),tn ft :asop xn}{
snfuqdos3
9.6tg - g,1arm1 :(Ag$ nC
ir , c-II\i.ro o.os[ ; 0t,\
- dtFa[ firnr1 :(Tfft{)
iC Oe - C-II{ :ool t ; 6iA
(,11O srlult(I E{Iltl ilel
+ iull tqiir.r) Eunl luuttoN
* orll]ldaslY tloIluI.Illj\
It]3o]o^rd.Iad
lsllt *iplruotr c
quunuli0Jq{II}d :lJIu}o.ld
r 1r t-.1

{ir'i
mrs eql {rr sai{ruqr uo fmp$edep efr{tuqr iuur aduqs (51-to) .15 aq1
".r*.J;;:'; ;;;i;;;;,,,i;r-;r,p 
,,,ro.ru,f,rrrr aq o1,i1r,1'1 sr a.rarrr r,rp s*.rrdurnssu
rr rr1{ a r\alllt"l:I 
:n l{1fi
"qf' "*rir* f .l ruacla.r arll rrr passarBar sutl AJ$l .Io ,\1D a{} 1I lla;ta perllpal aq io{I
prliCIrrs Lffi;;;3i;;,;- ,lq1:.nuqon *r y_*1i, y]Tlllllf"::.:'\t?jll"::::11,1,:IH
!')tlri,.j;)ii;ffi r,i,*ffi.,li; i,d; .{eru .11e aql q;i.oqf rra^r :a}orr 1uu1r,rtlru1
l
:'o,{ III J{xptlruIY/IoJolo.Id
quultlzIIo.Iq{II}d :f JIlp0.td
'pelu3l, eq plnotls
j\fd Arau u plru 'ur6.rcm + AICiAfoLrAau atl] o] palsnlpu *q prlolri j\lJ aq] asB) srq] q
'surloJep lo..{ruoluuu.Iaqlo o} e'\Ilqar sglqs AL5l aql;t ilussaf,au aq oslu Kuru fumrolrroca1
.amus aql rrruular pltloll$ Afd pIlE trffilol ,\I) aql lttq'uotfa't Panloltlor ilsnonald
"qt ur,pi* irto1"*1, uo,*t"rd"i rorlltufl parlolilo]-a.I aq plloqs .'\1$l ro AID '''\lSI
.ro A"'O,e-nlolro:).d11uurfno atll eplstno,*,ig ..' ar1:iaqt ssslrl 'soollu)lI4)ottt a"rrnba't lou
op,,\lCI,o IJD'(palurqe,ra furaq,(1tua.ur",, *, ,rru,,*'iuarla: aa.n1l aqlJo tl)III'{\ ur: n'urptladap
'i.ro t) iru.rs aql;o Jaqrunil anren^bas aq '(q Pa;rollol auluu arlurruls
aqt nq pelorrap aq lbnm UYg uu ol suollurlllPour ;(uy 'papae$ sB palJIPc'rI eq III^\ Puu
,rnrr,.iq,l u r(q pa,ltar.tal aq IILI\ sUYO reqlo p$u sfurrl 'p'ror lutrrds'r\I13l10 1tO a{Ll :
lura1s,is .LH$I ipep s1r.tro lrcd su ltlanqsttfpu
-1o aclir sql tuaulalcku ol papaau luarudnrba aqt suq uolIrlltsul atll Jl-auop aq '{pr: Pllloqs
oi,*rg nql oi safrruqr luuolluloU 'suuri l.) |uada.r ,,lJJo uqlu'u-slfat afutur 'IoJ pssll eq III'tl
1Oo.rp-puu-f,r"r1, 'iurqrio,,, *rl*"f1;os "Errrqrlern auoq1 f,UOI ..rllup ro'l Pasll aublmllal uoISlU
arrcs arll .rrur$ IJ luadar aIIl ol pa.rlaJstru$ aq III,'\a sUYq pul] uuJs {IoIluIlmIS luuduo
aql uro{ slai.rcl ,q, pitJp-Errnniuld i11r^t itnluru prEr: u o6:a1:tn llIA\ nuss I) tueda: eql -
Stttutuslt{at rct ltitarr zttp tb ttotlt}ttlttL$IaQ
'pant 8uraq,{Ealu'l}s luauraSwruru uol}oru aq} ttodn Eurpuadap
1.1Eu*ruu1c{ lerlpy e{ll sl31'rr.'p1o,t-itlserq'Cf) adA} atucs aqllo aq lll&r s1; teadag -
'{COS-pf uaa,\uaq puu r(9 tf-ge tlaa^uaq sl pCIlai\IlaP asop
aql amrt aql Errr.mp.m)3o lsrlln snlprq* Smluaclo.r luuoltlppY'papuatlmlora'r '(lEuoqs sI tui's
IJ tr0I}u.rUIJi;\ |Il3t1l|tsa'u-a.ril8 'a}8p tlol}Ullltttls eql ItIoJ.} a.IotII.I0 s..{up y1 Sl 3ll}p Etrlyuls
a(ll lI 'alup l.ruts luau4eal] peluruIls" ,q1 ot rot:tl s;(up 1 i uu{l alotil oU puu a}up Smgu}s
,,1f oi alqrisod su asoli) su -nlf,Jo oI ,a*Waqrs aq pinoqs rrurs Eu*mtl1d tt':tlelnnrts IeIlruI
aq1 .uu1cl luauuuaJl ra{Il ol suolleJglpotlt sa.mrt a-l }rtartud 8 .Iaq}a([At ssassu o1 panutTrad
eq IIIjt\ suuJs IJ tuader 'r1u.,.q*.l1.1o Eurrmclt{ .Iof pemu}qo slesu}uP 13 atll o} lIoI}IPp€ q :
t ut t t rsr tt Is tu J3 wadaY
sa8urqS tlruotBuv o1 ddrraqtrorpruldrpy ol susls 13 lradag as'Ino)-Prlt 8I'I'S'S
'pannba.l
sr Eurfsllu dlrup'1oro1o.rd aqt m palul$ sui:tsrmr{xa AId aq} q}t'u aonurldnlo} oAeIq}B oI :
' 
l.rorloilsrBal a8eurr .rof, slool alu,tuJios ,l,olckrra puu Buluotltsr;d luaqu<l
.ro.y strralsds Surf urgr ,(u.r-x luuoiolil.Io ePnp{tl }snur slffin asall} 'unltrrlllnn u ;y -frrutollrsod
luarluil Jog rualsds irn;ugl Palmrpap Jaqlo .lct 'slru'I-n(]-l) 'r-utdutttt pltsoq-uo tlll't\ sallo
ap*la,,, slrun q,rs .saqqrqudur iruuprrrf a6ur.'. rltr^r slltnl uo iltto palua$ eq IIyA sluetlud -
'(ssa.rtl trr iuq.1u1) radud atnlt\ IUDI
0f
l..!lunp:l$o) c

srruldal antldupP
atp alutull$a Dl pasll
aq] laam pploqs ,rr,ro slr uo 'rrBICI A\;u arlJ 'rltsld Ara{t aq} Jo lrol}tszllul}do PIrB l1slsop aq}
m pereprsrroJ lolr sr elsp ol pa"ra.\Ilep asoP eq.I. 'tiluetnlee"q a$lo 'Iepliluruel aqlJo 'fta'r'qap
pur) uortE{rlB..ra ^roJ pasu aJts suqd paqrpoul a{l} Jo tlsBa tlo pedultlstp snollnqlJl$tp asDo :
'uui,slqA 6urlea.U arllJo uolla.Icstp atll tu aq lll,u Strnmulda-t'1"9'g lrollias
ilr alqul arll w pagrJail* ur"rr]r.r, {Io pasuq uol}t l.\ap alquldacrunll sa}uJlplll afurrn "t\au aql ol
,rorlorruagno:! rggeq luurino aqt qlr,\\ pCIIulnrlu..l asop aIIlJl 'sallssll IurIlIJc s$al 'Je{llo:oJ :
'iror*rr.lsallounu ol allp l.rcaq ol looqslen'o uolold aq prlo"l\ alcltrruxa 'IeII"loIrV'B{ml
lurtrto(I aql oiul b-ttt;oor1s:a.lo frttsttu-l lloll:)llpaI 1rrclr;rtUils pBtl Jr3 ilult'rul satt1oleq ''OUnU
arll tr,{ll }uaAa erlt ul uelcl lirr8r.r.r aql q.{g U I sE^\ O-Jtr1l ueq,q uulcl uotlurgl^Ia.\ agl uI {C ll
g1trrg:aldurgxa JoC 'uulcl lurn6rlo aql ol,IoIJaJ{II sr nuld uolfl?rlJl.Ii;\ aIIl uollrl\ allop aq plnotls
*iA lu."rfua.rl r].Io Eultmuldag :uuld IBmfIJo alll {lll^A pa'rudntor uol}llqlJlslp asop 'IoHaJtq :
'AO0Z4j.
a)-op SrrnJ rruirr Jo 'c6g[.::Qfl Erml ',13 [$.1(ergg'61xuttlc p.toc lutttcls all] Jl PauuoJ'rad aq
lsum suvo aql t)l sasop raqfrrl rr0 passq {IEId l{rem}Ba.I} BJO i$nnrulclax :aftopJe'\o uYo :
'rrulcl u,:rluoql.IeA uI alqutclarcurm uollslnap sil\oqs afu.ta",r.or la6lul aqlJI I)amIOI:ad aq ;xtut
rnfr.rur'"qtlo aduralol rapun rro pasuq uuld 1uau1ua.q uJo $wmluldea :afru.ra,tor.1aflu1 :
pelu)rpuI
sr rruldal .rarllouu lrlull Jo luawlua.Il aIIl Jo lsa.I a{ll .IaJrtlap ol P$sll aq IIIA\ sltll puu asop
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6umrumai aqi qlr,n rref,$ $\eu erll ilo ulrld er\IldBpu {Iu aluali 'palu)Ipul st uulda.r 31 o
'IIIU tu pe.Ia^Ilap sr uuld Iumf l.Io aq).tr1 TTBJS fnrtmuldal
aql {ro HIC r{ aduuqr,rtrc sr eJaqtJI a}unlg.\a ot attop st snlJ'uurs furtnru1la-r aqt
uo asop gorl6ulsalcl IIIU arll rltrm uuld lutttitlo aIIl ulo^q llollllqr.uslp asop aql alua'rJ o
aJua;alar su asop rrorlch.rrseld 1yg ol uers JuurEt.to etll IIo uulcl luurdlto aql asil o
:sue1d
a.trldr4tu aql attsa,It ptru suuld trol]ui]l]IJa..r 3]ul1lB,la o] uellul aq plllo{ls st{a}s 6ttt,trolloJ a{U :
'durrmulda.rlo luod aql sI lrlql lt"tq'alqeAarqcB
lou rr srrll sarml t1' 'H, O s,rruld lum8rroysrrot..ra:cl aql ol il.ltti)lrrls luIU JoJ II-\0 aql arol$e"I
ol apuru sr I0JJa,{.ra,ra'uu1d uorluclJrJo,\ arp m 1aBlu1i0 uYo uu ol tlounqluslp asop tr
a6'uut1:r 
"iqu.r.-,,ougrt l uu sl a.Ie{l} Ilatl\\ '8'urtruuldartro paau elp uo al}IJap prru rruld tIoI}u}IIua'{
aql elpllu^a plnoriu rrurus,iqcl Brnlua,q arLL 'uoltrt "Ilt8tluor mcaq ltla.lilrp u aseq ,{1ary1
.{.la,r 11lr* iI 'r,.rrlr-r, paryrrar{s erll taarrr ol pauElsap ne1<I ararr u st truld a,rrtrelupu tly 'alquldacru
llrls sl uorlnq1rlsrp asop aql Jatllaq,{\ AJIlaA ol ttotlu.lttbtlttol (uru.rq }IIa.LIllJ.lIIl.Io} lutrr8rlo aqt
fiuu a6u6u ]uadar &1arr atll Sursn palncluroc uorIlqlI]slp asop qlrrrr rmlcl u sl tluld uo]]Bf,lJI.IaA Y
r&ll ttuttyd aa1dnpul StttttttttSdat puu ttttld totltttg!fua7
'sa.nu)rqs la8.rul PIIu sUVO e(ll
"roJpa.lua"I)aqIIIi\sFI^oJ{)}as,{tatlBp{ru'palulllf,Iu}aJa("lua{ItIlrrt\(I{:,IlllqII}SIpasopa{I}.I.)
ioi,tr., aql ol paxaJsrru.u iQ 1p*r uulcl lrrarutea.u pe:rordclu (lstrot,ralrl all] ltlo.g ('rla 'sa.rrutadu
.slqlusuaclgoo 'slqdrerrt 'sdAOS 'sarf.raua 's{IoI}Je.1Ip uruatl ) ttollu.nm'gtt,''rJ tlltsaq aql :-
parunssu 'S r{ae*\.{o afruwt -i. ; a{} rrl parlddu aq lJI'\r s}{ra{uue$ Jol pesll
a{ll ptlrJ luurfuo ar[] "r.{ suollu.nrdquoJ-tlluig "sIIOLllt('ll.IliIp asop paIIIIlIns
aq 0l sr e.mparolt{-6'ur*o11o1 aq}'sutsld alldupu fuumba.t s}uaqud.IOJ :
urrelil.r ellssll IullHoII prtu adu.ta,ro-:l ladJul paqr'rads
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rrorlulpurfo uollaldruof, aql Itlmt,iup b 64 8ru 961 alozutrocnlS (1
UO dup b 96 fiu 00i alozerro:ro1a; (1
sp;Srqdosg uoltr!pBU go luauraEuuu6
'Arolsq
alqul arlr trr papr,torcl a"rts sluetrque.rl pepu;urllo:)ag 'dlt:txol luaSurlclosa 3,o snrolduris lo sudrs
ls.rq ;ql lu pelurlmr aq pliloqs pw qrBCI.rdtle Ern;lro11oi aql qllt\ pa8uuuul d11ucrf'olorulrrBqd
aq plnoqs ^cla 'surotrflnds xngal "ur8uqdr:rr{po 'utSuricls,{p su slsefnlum puu
lneuqtsa.rlfo uorlurlltrr e{llJo s{ee.,u o,t\} mq}I^l.II1JJ0 trui:(11u:rrd.{t {li}I{lA\',urrtx0l lua8uqdose
allrf,y urf utldt:nIpr:.ro urluqdsdp .ralua.rd .ro p apu.d lo; peldtrualtn eq plllolls luatrqua.Il
'.nloclqul '.lg ,gr1ou asuald 'luaAa slqt uI 'palclru:a1tn luetulua-Il raql
a,ruq duru srllBeqt{ose fo s,$nuJaq noquzrlulrdsotl Etn.rmbe.I slltal}ud 'ssal Jo siup tuauQua:t
t ol Il l111rll ol apuur aq plnorl$ poga trrala 'FaJeprsuo] 8tttaq u uotlt{rrua}rrl luauTluerl B prlu
.s.il13lo sgrduqdosa (t '.1 'EV.:t;) p apu.rgSI 's{ee.u g-f IoJ }stslad,tuttt stltEctfIosa aprry
'pa^rrnbel aq .{uru sot}rf, i-Itsu'{luuorsse:rJ0 IaIIa"l ctluruoldttt{s "ln3
pe$t eq plnoqs suorlucrpefir Jerllo.Io efBJB.ruJ'amrro1,(5 snoJst.\ 'sar-ula.raq.ro spr:o3 i(rtds
Jo 'Jrpnlu 'JrlorloJlu prCI^B ol pesrnpu eq plnoqs sluatlud uorlulpiq {nulIIIBtrI ol lualJgJtls
sl a:{ulrq IB.ro paprAord,(dulaqlourarlf, -ro d<Ie-raqtorpu: r(u1ap:o }rhlualm o} tlosueJ u a}rql}srloJ
lorr saop srlrBuqtlosg 'irlu"raqt r$rluporu pamqrror rlllnl ltoltnrloJ ars slutulcltnoo lua$uqdosS
sqrBtqdosg 0Z'I'!"S
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IlroAt] ol ^rap"ro rlt alqlssod su funl Jurruou q)rrfiI su a.ludr o1ltsIlltassa sr ]I 'lue(utsel]
JO rrorlurtrur.ra{u $rtr}rroru [-i lsJrj aq] wq]IAil ua$o lsotu puu slpllout 9 ]srll aql urq]I^\
,(11unsrr '.(C Of i fur,rraral amnlol frml nupr,tr JlnJo JIIA\ Eunl aql Jo sIso"IqII lrtarrbasqns ptru
a&luqr uorlurpul Jo al$aprr\a arqdu.r8orpug ,{D 0S uuqt Ja,trol sasop }u JruJo ,(1alel stlt1a{ui
as:eAsuuJl lo srllplurodur pecnpm uorlurpu5 '{du.raqt {Iorlulpe.I Jo stiEJJa aprs palcatlxa a.ru
srlrfuqdr:sa puu 'uorlul{raurdrd urls ',(lrlrxo} ,r\o.utsttl att<lq'utradolB lri}Irululad.to alqrs,ra,taX
stuorg e$ranpY tduaql uollrlprll 6I'I'S'S
'pasrr sB/u n0llnql.qsip
{lcBa srtor]f,uq Jo Jeqrurru aql ot 8ruploaru patrtpta,tr pallrrlns eq IIIA\ sttotturudguoD eql Jo
q)ua.roJ palrrdtrroc $rrorlnqulsrp o,sop aq1 '{duraq}olpulJo as.moJ atl} Ja,\o .{utoluuu e6ula,ru
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'tuafiuua.rlJil r(up aqt uo.{clu.raqt uorlr]rpu.r aq} o}lotld pelarllap aq pplotls {du.ratllr:rueq-1aqJ.
sJIlaltlelllru p.IE)truls IJIIA\ saltllmrl 0f
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(urolsnr IBJ6I ol Suprotru alqutrdamu sr sllouirrt)gur:o p.ro) a$osuqlallrBxep pilu'.Ia{lolq-[H
uu .6ru 6S-Si aunuu.rp.dqrraqclq:3o Srulxrsuor uollullpsule.ld p,tupuuts qll^\ .moq 1 ra,lr-'' ua,rtE
aq IIIA\ 1axu1q:rucl aq1 'tlpp snoualuJlrrr dq dlsnoue-,ru.qlll pa.Ialslultupu aq III/t\ situp 11y
M!l6Jlslultupy idrraqloruaq)CZ'I'S'S
asop urlu1<Ioqiur eql Jo rrorltsltrlluca.r I l{rB.LIr}Ar 11trrr 'aluu.rual.! eturll}8a.I} pelull}luJ
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'penl aq os1u.,{uru uollf,elloll etllrl rloll te ts ulor1 I.)"r) ps.mseattt Y
'ssa[ aq ,{urn 1l
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arll'a.rofa.rarl1 'unrr,,Jnr 0SI x (1ur,iEtu x fru)^1ny le6rul:(fltl) asop ur1u1cloq.ru3 t{Illtrlxl}}{
(tpi6ttt)
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:'urtu,.-Jul sII paalxa
lotl pltloqs ptru (*ro1aq) uollurrba llnu9{o.r{3o) aql6ursu patrupl;}lur aq plnoqs I.}.I) aql
[(Sf + I.)-r.)) x (;ttV 1a6:u1) =
(iur esop ullulcloq.rur Iulo1i] Blnuuc{ }ia^lu ) aql ftttstt patB}l-rlul aq plnoqs asop urleldoq.ru3
asop uglrltloqrr) IU'I'g'S
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IBrrJoJuo)Jr: sr{up Etrr*rogo; aql uo urluldoq:uc ptru laxu}lloud aqt o;\toJo.I IIIA\ stuallud
'(1,tr;g:.1ny) rrrluldoqrur puu (rytrigrl,rfq1 65) laxutrlaud aq 11r,tr {drraqlotpgr lguuoJuo)
q1pr,r filuaunruol ua.rrd aq ot.,{du.raqloruarpJo sasop eql :.{dr.raqloruoq) }ua.rJn}uo)
uollBrlslulrupy,rduraqlotuaqJ lue.Irn)uo} II'I's's
'stlt6utldosa g apud a:rnauadxa 11t,,n s1uarlud.1o rr:l1lr:d luurgut8ts
u lradxa al.1 'ssal.ro g apu,6 1r1un.{dularllorueq) + JU plo{l :srltBuqilosa f apul5 (S
uollulprr^I lo uotlalclutnr aqt lllult (alozurclauto
su rlrtlslottqnpl r{tuutl tto;ord u .r0.rs{oCI1q eH.Iaq}o.lo) OIg 116 6ttt 0CI aupl}Illug (f
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:n uitt*;u,{axl ;e.gu pe.{rasqo uaeq sBII IIoI}nlos m sJaqq Jo .Iaqtln}tl Ilums B -}o {Iolluuuo.l
:Il-Ol,l .uortn.rt*,,r,r.ipr,'a.rogaq'dlaturpaumr palucle.ttl a("1plllotls al[ot]rduq IIrBS 'pazlllqnios
sr 1axu1r1.rucl qcrrl.,\lu alJrqa.,r:loqdotua.r.1 atlt,iq 6urqn1 $uoue,'tuJllll ptru s6uq (;,ra)
aplro*' lXui.urtloO uro.rl ijrrrrtsuld (dH3C) a1u1uq1qdxet11.{tlterp 3o 6mqrual ol arrp sreul*11loi]
' ' ,itl"ioiiocl q..os as.i1 (;oo t ':1oxel o.tru1 po.r6) 8,r1r$r1 moo.r ,Iru (srus1a3 saar8ap g1)
a.mlurackual )lretqwu.rsprill s.moq l[.Io.] sJqBls sr nol]I]los snll 'JalllIIIItIlisIIru'r*IIIIul rI ol ['0
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.dsn eso.ltxap o.,i,s qlr,!\ rroQu$smrlupu aJOJaq palllllp aq lxlut uotlrallu -ItI laxt]lllrud 'asjn
luriilTor ror"rcllsrif p"Itllry aq l$1m IBII arllJo slllslror a{I'o'ir0S"dsn'lorlorlu palulpdqap
puu gtOE (1g.ror1cloura.r.1) yo rotsur pelul{q}e.'fxo{1od m (lut.t,fru gg) s1ul.r' IliI E uI Imrdm 9
'altsrrraf,uo; ltorlrrlos allrals V '(J"tt-*9t) J"SZ-*e uaaAuaq pa:ols aq pltloqs sluIA JaxBlrl)ud
uollarutlard lsxElIIrsd SU'I'S'S
's.Ilorl l; .Io.I alqlJls ,(11uoltuat1:t
prru;(11uors,,iqcl alu (pn;8nr z I-t 0) 1axu1rlrucl.;o su0llulos'a,\oqtl paql.I)sap su paruda:duaq,n
qdloqtlu'n,:rtulldard r"$u p"i.lu1" riurl ailt puu drupgo ltoliu.Ilnar{Ior alp o11uttoll"to<{rxd
,{1t:ra.ilp ssarnzuq tq6r1s u llqHxa 1a:iutrqtudlo .$uollrllos fiY 'aJII Jlaqs q}I.^il palaqq
3q IIIA'\ slBrA '.Ialuill III a$Ol:{ap g.is Jo apI"IOH) Unltpos 0',o6'0 Jaq}Ia tro stlounllp 'IaII}IIT
qt,^ i,r.t*i, i,irnlor paxmt u sarttlral grlrqrrlos paler.tr{ru1 'ut1o!*tqs',r-\,rJ 'rna,t rttrtou4
arll m0{ lrtt'portl yn:1<I alqrqos l.1.rood u sr lI 'Sil atJl tII alqulte'ru 'i11utr't"rIIIIIIo) sl {axu}IlJud
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aql ffi pegriacls su arlurl{r{)lllr,t {ror}}alloJ ts}t}p pue citt rt\ollol 'pellul}uoi}slp aq plnolls
luerrlgaJl 1oco1o.rd 'sdup g { uuql .laEuol "rcr.tr parnba.r eJu s{uarq luetlll8al} lI 'peluafinl:]op
aq IIIA\ 1ttq drr apuw aq lorr llrrril ,(clu.laqt uonurpts.I qlt$ lrrarltlf,IloJ altlPall.rs .(11aa,tr aqt Ern-ntp
passrur aru lerll saso6 '(,{upsanl Sur,nolJoy atlt ualrf-aq plllo,t asop dtlu:atl}ouetl} lxau eql
.,{ug.roqul uo slltsJ asoP S dup aqtSr ''a'r) {upqrlq arp 6trr,tro11o3 dup ftrl.ro*r IlnJ txau eq} ut]
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su pa.luclercl uaq ypu,'ful 0l l0 tIOIllrIUe-llIo'1 tttluleloqlur u a:rttpi-xcl IIU suoUnllp isaql
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Protlrrct: Pelrrbloliaunab
Profocot/Arnenrlrnert.o.r f 
, ,
G Conlidrnriat
Subjects shotrld be inibunecl that takiug the shrdy uretlicatiop gray involve tnrlorown risks to
the fehrs (rurbofrt babf if pregnill]c]'' rvJre to occrir during tlre .strrdy. Iu orcler to participate i'
tlre shrtly tltey tlttrst adltere to the coiltraceptiou ,,"c;,,ir*,niri1d"u.rirru.r above) foi t1e dtuation
of the shrdy anrl duin€ the fbllorv-up periocl defuieti in sectic,n ?.2.2-Repo11i1g of pregrra,c;*
and Lactatiou to the sponsor alr.l to tv{erck^ If there i" a"i, questiou that a sutrject will uot
reliabll'cornply u'itlt tlte reqttireurents for crcntraception, that sgbject sho*l6 n.t be entere<l iuto
the study.
5.7.3 Use in pregnancr
If a subject urach'ertentlv lreconies pregnant while on tleaturent rvith peurbrolizumnb. the
srfiject will inrmediatel.v be renrovecl-fioL the shrdy. The site rvill corrtact the subject at least
rnontltly a.d cli:cttttttrrt tlte sutriect's srahm unrii the pr:eg1arrc1.il-;;;; IJirrpt*tua o,.
ter:riirtared. The otttcottre of the pregneilcy will be repfrrJcl to ilr* spoo.oi ,rra to I{erck
rvithout clelay arrt'l rvithin 2"1 hours to ilr" Spor,ror anrl withil 2 rvorki*g clays to lr.Ierck if the
otltcolue is a serlorts adverse experience (e.g.. cleath. abortiol, r:ongeuital anouraly. or other
disabling or life-tlueateni,g co,rpricatiou r,", iLu mother or newb.rl).
fte shrdy investigator.rvill_urake every ef'fort ro obtain pemrission to tbllow the outcoure of
the pregnancy altd repc'tt the conditioir of the fetus or irewbom to the sponsor. If a ,mle
subject intpregrmtes his ternale partiler the shrcly persorurel at the site uust lre iufcrnnecl
i0Inediately and the preguailcy leportecl to the Sponsor and fo trr.ferck a,rl tbllowecl as
described abol,e arrd iu Section i.?.:.
5.7.{ Lrse in l\ursing \l,omen
It is unlarorvtt rvhetlter pernblolizumab is excretetl ir hruuar ruilli. Since mauy cl.rgs are
excreted irt hrtnrau urilk- aud lret:ause of tlre poterrtial for serious at{r,erse reactious in the
nru'sing iDlhnt. subjects w{to at'e breast-tbeding are rrot eligible tor emollnerit.
5.8 Subject Withdran,nl/Discontinuation Criteria
Subjects ttray rvitltdrarv cottsetll at anv time t'or any reasou or be clroppe6 {i.',r the trial at t1e
discreliott of tlre ittvestiltator sltoulcl au,r,. rurtorvard etl'ect occr.u.^ hr adtliriorr. a subject rnay be
rvitltdrarvn bv the inves{igalot c}r the spousor if emr:llurent irrto the rrial is urappinpriafe. t5e
trinl plarr is violated. or lbr atJruinisirative andlor other saibty rca$oos. S1r..ii. cletails
regar:ding discontiltmtiott or lvithcL'awal are provicled in Sectior t 7 .1.4* Other procecltues.
A subject mrtst tre cliscoutittted li'oru the trial for any of rhe tbllowilg r.easous:
e The 'strbject or legal reFreseutative (such as a parent or legal guarclian) withch.arvs
conselIt.
o C'ouiinnecl racliograplric cli.sease progr.essiou
44

Pt'otlttct: Peuttrt oltzttntab
Protocol/Amencllneut nr., I, 
-,
C 
Gonfidt*ntial
ifote: For uncoufimred radiographic disease progression, please see Sectiorr 5.2.2
:Yort,: A su['{c-ct ruay te grzurted an exception to corrtir}ue on treatrrtent rvith
confinnecl racliographic progression if clinically stable or clinically irnproved,
please see Sectiorr '7.1.2.7.1
r Uuacceptable adverse experiences as described in Section 5.2.1.2
r hrlercun'errt ilhress that prevenls fiuther adruiuislration of h'eahnent
o Ilvesligaterr's ctecisiou to withdra'rv the subject
o The sutrjecl has a conf'rnrred positive $enul) pregrtattcy tesl
r Noncompliance ivith tlial treaflnent or procedure rcquireureuts
o The subject is lost to foll:w-trp
o Corupleted l8 closes of pernhrolizrutab
,$ore: /8 dosed oJ'sndt trcclicotiau is calculated trout the date offirst dose. Subiects
who stop pernbroli=ottab after lB doses may be" aligible/ornp to one.year of addilional
studv trentrnent i/'tlrc.r' prcgres; afler stopping sfidv trealnewi profide.d tlwl, nrc,e.l the
requireuunts de.tailed iu Se<'tion 7.1 .5.5
r Adrrrinis0ativereasorls
The End of Treaturent and Follorv-trp visit procedures are listed in Section 6 (Protocol Flor,v
Chart) and Sectir"ru 7^1.5 (\'isit Requileruents). After the errd of lrealmerti. eactr subject will
be tbllorved tbr 30 clays tbr Rdrrerse event monitoring (serious adverse events rvill be collectecl
for 90 ctays atler tlie end of treatureut as described in Section 7.2.3.1). Subjects who
discontinue for reasous nther than progressive disease will have post-treatntent follow-trp for
disease stahrs rurtil disease proEesslon. initiating a nou-sftrdy cancel' tt'eatlnent. rvithdrarving
couserrt or becouriug lost to fbllow-up. Atler clocuruented disease progressiott each sutiect
rvill be fullowecl try telephone tor t'rverall sun'ival rurtil death. rvithrt'awal of consent. or tlte
end of the shlcl-v. rvhicher,er occtus lirst.
5.8.1 Discontinuation of Stutly Thertpy after CR
Discoutirruatiol ol treatulent urav tre r:onsiclerecl for sulrjects u'ho lrave attainecl a conf-tnnecl
CR that have beeu tl'eated tbr at least 24 rveeks rvith pentbrr:liaturab and had at lenst tr'\,'t)
treatureuts rvrth pernblolizumab be.vond the date u,'hert the ilitial C'R rvas declarecl. Sullects
who then experieuce ladiographic disease plog,ression may be eligible frrr up to oue year of
.15
aclcliticural treittlrrenl rviflt perubroliauna[r via lhe Secr:ncl Cotu'se Pltilse al lhe cliscretiorr of lhe

Ploduct: Pertiliroliztutub
ProtocouAmenttrnent .o., I, 
-,
C 
ContidGntial
investigator if uo cancer treatrrlert rvas adrninistered siltce the last dose of pernbrolizuurab. the
subject meets the sai'eh, paralrletel's listed in the LlclusiouiExcltmiou criteria, and the trial is
opeil. Sulrjects will resrune therapy at ilre sanre dose and sclrclule at the tirne of initial
discoutinuation. Adtiitional details ue provided in Sectiorr 7.1.5.5.
5.9 Subject Replacement Strategy
A srrbject who cliscoutittues ti'onr the trial will not be replaced.
5.10 Clinical Criteris for Earl-v Triql Termination
Early hial ter:nination r.vill be tlte restrlt of the critetia specified belorv:
1. Quality or qrmntifr of data recordirtg is iuaccurate or incotuplete
2. Poor adherence to protocol and regtilatoty reqtdremen{s
3. Incidence or severitl of adverse dnrg reaction in this or other sfudies iudicates a potential
Irealth hazald 1o sutr.iects
4. Plans to rnoclifl,or cliscottinue the development of the stucly elnrg
In the eveut of Nlerck decision lo uo longer supply study dnrg. aruple notification will tre
provided so that applopriate adjusturents to subject trealrneut carr be ruade"
1!

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