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| Official Title:        | Moving PD-1 Blockade with Pembrolizumab into  Concurrent Chemoradiation for Locally Advanced NonSmall Cell Lung Cancer (Multi-Center)                |
|------------------------|----------------|
| NCT number:            | NCT02621398    |
| Document Type:         | Study Protocol |
| Date of the  Document: | 10/21/21       |  
$. conlidantisl  
  
Princioal Inlestisntor :  
  
(loncurrent Chenrortdiation 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 t't' l\. t, t  
| Abbreviated Title                                             | A Phase I Siutly of Perrrbrolizrur:rab {lv'lK--l4?5) aud Concrrn^ertt (lhemoradiariou for Nou-Srnall Clell Lrurg Cancer                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
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| 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- |
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1.0 trial st'}i}iary 2.0 trial

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'.  
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 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 nottsurall cell lung cancer.
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2.2 trinl diagrtm

The trial design is shorvn iu Figure I  
  
Figtue I Trial Desigu
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3.0 0bjectm(s) & hypothtrsis(es) 3.f

(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
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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
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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
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.i.o background & rdtioiyale 4.1

Retbr to the Investigator''s Brochure (lB)lapproved labeliug for detailed trackground infonuation ou IUK-3'175.
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.{.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-  
  
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 nonhernatopoietic 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.
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4.2 rationale 4.2.1 rntionale for

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) ^
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.1.2.1.1 rationlle for pd-l blockatle

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-rtl\t': t.' L 11,1.i 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.
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4.2.1.2 data supporting concurrent immunotherp-v

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 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.
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4.2.1.3 clinical data in support

PD- I blockacle irt locallr, aclvartcecl  
  
I
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.  
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  
  
  
  
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.
untitled h1
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
? rse relationshi rrrg.lkg ol l0 rngikg Q3\[I in ntelanonta patierrts. l) the t)at expostrre-t  
  
  
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.
untitled h1
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).
untitled h1
.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.
untitled h1
{.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*.
untitled h1
4.3 exploratorvobjective 5.0 methodology 5.1

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.
untitled h1
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"-  
  
  
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.  
rlt)
l\ I j 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.  
| 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 : 1.5 X ULN 0R                                                                                                                                                                                                   |
| AST {SGOT) end ALT t,sGPT)                                                                                                        | r,r'ith liver lneta!I.ries                                                                                                                                                                                                                                                                                      |
| 3 5 X ULI{ for rut                                                                                                                |                                                                                                                                                                                                                                                                                                                 |
| Albrurrin                                                                                                                         | :'1.5 urg cll                                                                                                                                                                                                                                                                                                   |
| ( o:rgulatiou Lrter:ratiotal Nonnalized Ratio {I}iR) or Plotluonrbin Tinre (PT)                                                   | 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 .A.cti"..ated Partial Tluornboplnrtil Tirne (aPTT)   |                                                                                                                                                                                                                                                                                                                 |  
Table I Adequate Organ Furction Laboratory Valttes L Forced expiratorl blonchoclilators by yolume .' 1^0 L 01 ;," *Oo.O
pulmoilaryI fituction testing.  
of preclictecl lvith t-tr w:thotlt  
  
  
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
untitled h1
5.1.3 subject exclusion criterin

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.  
6.  
- 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.  
  
1.  
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"  
  
li. No active $econd cancel's
untitled h1
5.2 trid trentments

The treatment to be used iD this trial is outlined belorv in Table 2  
| Rorrte of        | Regitue* Treithllelll                                        | Llse    |             |                  |               |
|------------------|--------------------------------------------------------------|---------|-------------|------------------|---------------|
| Dnig             | Dose:Pottncv                                                 | Dose    |             |                  |               |
| Frequency        | Aclurinistratiott                                            | Periocl |             |                  |               |
| Peurtrrolizurrab | ?00 mg or 100 tttg clepeuding on trial scheuta in tuli::ll:1 | Q3\\,   | IV iufusion | DayIofeachirveek | Expelitnental |
| cycle            |                                                              |         |             |                  |               |  
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.
untitled h1
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'
untitled h1
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^
untitled h1
5.2.1.2 dose motlificttion

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 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.
untitled h1
table 3. f)ose llotlilication rntl

| 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* corticosteroidrToxicitl'                           |                                                                                                                                                                                                                       |                                                                                                                                                                                      |                                                                                                                                                                                                                           |
|---------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| lmrnune-related AEs       | grade or conditious ((:TCAf,r' -t.0)                                                                                                                                                                                  | Action t:rkeu to                                                                                                                                                                     | irAE m*rngernent                                                                                                                                                                                                          |
| pembrolizurnnb            | rvith corlicosteroid nud/or o(her therapirs                                                                                                                                                                           | llonitor nud follorr-up r lvlorriior pafiicipanfs for signi ald s!lrlptonls oI prtetuuortitis . E','aluale parlictpants u'ith strspectetl prteturtonitis u'ith radiographic inraging |                                                                                                                                                                                                                           |
| Grade .i or               | aud iuitiate cottico,'tet oid treahrent                                                                                                                                                                               |                                                                                                                                                                                      |                                                                                                                                                                                                                           |
| .1. or                    | r                                                                                                                                                                                                                     | Adcl prophylaetic arrtibiotics tbr                                                                                                                                                   |                                                                                                                                                                                                                           |
| re!'tu1'erlt              | oppofruristic iufectiour                                                                                                                                                                                              |                                                                                                                                                                                      |                                                                                                                                                                                                                           |
| Cirade ?                  |                                                                                                                                                                                                                       |                                                                                                                                                                                      |                                                                                                                                                                                                                           |
| Pnerunorritir             | Grade l                                                                                                                                                                                                               | Withhold                                                                                                                                                                             | Atlnrilister corticosteroids (initial dose of 1-f nrgr'lig predrrisone or etluivalent) {bllowed by taper                                                                                                                  |
| Pemraneutly,' discoltiuue |                                                                                                                                                                                                                       |                                                                                                                                                                                      |                                                                                                                                                                                                                           |
| Diaryhea ,'{lolitis       | Grade 3 or                                                                                                                                                                                                            | 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" |                                                                                                                                                                                      |                                                                                                                                                                                                                           |
| \\'rtlihcrld              | .{dnrinister cotticosferoids                                                                                                                                                                                          |                                                                                                                                                                                      |                                                                                                                                                                                                                           |
| -1                        | {irritial dose of l-3 urgtkg predrlisolre or eqrrir-aleni) lbllou'ed tr,v taper                                                                                                                                       |                                                                                                                                                                                      |                                                                                                                                                                                                                           |
| Crade {                   | PennauentlJ' cliEcoutilnre                                                                                                                                                                                            | t:\ I!                                                                                                                                                                               | i                                                                                                                                                                                                                         |
| til                       |                                                                                                                                                                                                                       |                                                                                                                                                                                      |                                                                                                                                                                                                                           |
| I I                       |                                                                                                                                                                                                                       |                                                                                                                                                                                      |                                                                                                                                                                                                                           |
| il;rptr;itLrrr Lltle      |                                                                                                                                                                                                                       |                                                                                                                                                                                      |                                                                                                                                                                                                                           |  
  
C Conridsntirl  
| Cirlde 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   |                                                                                            |                                                                                                              |
|------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------|
| ASTl ALT elevatioll ot Irrcrtased trilinrbil                                                         | r Adurilrister                                                                              |                                                                                                                 |                                                                                                                                                  |                                                                                            |                                                                                                              |
| Pennarierrlll' discontiuue                                                                           | cofii(osteroids (initial dose of I -1 rugikg pre&risorte or equivalent) tbllowed br-. taPer |                                                                                                                 |                                                                                                                                                  |                                                                                            |                                                                                                              |
| Type 1 diabetes rnellitrrs (TIDN{l ot' Hyxrglyceruia                                                 | Glade i or .l                                                                               | \\rithhold                                                                                                      | . Ioili&te instrlin rcplacetuettt therallY for participalts with TIDN.l r Adrninister antihyperBlycernic it pafiicipiurt"s $'ith hlperglycernia                                                                                                                                                  |                                                                                            |                                                                                                              |
| Newly' ansiet TIDNI ot' Gracle -l or 4 hyperglyce rrria associated u.itlr evidence ol p-cell farhu"e | Monitor partic ipauts for hypergl.vceruia or other *igrrs arrd sytllplollls of diabetes     |                                                                                                                 |                                                                                                                                                  |                                                                                            |                                                                                                              |
| Hlpophl'sitis                                                                                        | Cilacle l                                                                                   | \\'ithhold                                                                                                      | r                                                                                                                                                | Adnrinister corticosferoids artd ilitiate honnotral replace[rents a$ cliuically indicated. | \{onitor tbr sigrrrs atrd *ynptotus of irypophysitis (ilchrding hypopindtmism arrd adreual irrsuffi ciency,l |
| Cuade -l or                                                                                          | Wiliihold or pellnartelltl-v                                                                |                                                                                                                 |                                                                                                                                                  |                                                                                            |                                                                                                              |
| 4                                                                                                    | discoritinuel                                                                               |                                                                                                                 |                                                                                                                                                  |                                                                                            |                                                                                                              |
| Hyperthl roidisnr                                                                                    | (ira<le l                                                                                   | C'orrlilue                                                                                                      | r Treat rvitlt trorrseleclive betablockers (eg. propralolol) or thionaurider as aooropriate                                                                                                                                                  | .                                                                                          | Morritor for sigls altd synpfoutr oI thyroid disorders                                                       |
| Gracle 3 err                                                                                         | \\rithhold or                                                                               |                                                                                                                 |                                                                                                                                                  |                                                                                            |                                                                                                              |
| 4                                                                                                    | 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.                                                |
| (irade l                                                                                             | \\:ithhold                                                                                  | r .{dnlinister corticosteroids (precbisone 1-3 ln8:ikg or equitalent) tbllorved bv lsper,                       | t                                                                                                                                                | Monilor changes of lenal ftulctiou                                                         |                                                                                                              |
| Ne1>luitis zurd Rerral dyshurctiorr                                                                  | Grade -1 or                                                                                 | Perrnauetrtl-v                                                                                                  |                                                                                                                                                  |                                                                                            |                                                                                                              |
| {                                                                                                    | dircootir.' re                                                                              |                                                                                                                 |                                                                                                                                                  |                                                                                            |                                                                                                              |  
| r                                                                                                                                                                                                                                                                                                                                                                                                                                             | Errsrue adeqrrate elahntior to confinu etiology alcl'or exclrrde other causes                                                                                     |                                                                 |                                                                                 |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------|---------------------------------------------------------------------------------|
| (lr.a<le 3 or                                                                                                                                                                                                                                                                                                                                                                                                                                 | Penlarrently                                                                                                                                                      |                                                                 |                                                                                 |
| 4                                                                                                                                                                                                                                                                                                                                                                                                                                             | discoutiuue                                                                                                                                                       |                                                                 |                                                                                 |
| All other irurnune-relatetl AE*                                                                                                                                                                                                                                                                                                                                                                                                               | \\rrthlrt.rkl                                                                                                                                                     | r Based on ser,eriry* ol                                        |                                                                                 |
| l'11'ocarditis                                                                                                                                                                                                                                                                                                                                                                                                                                | Grade I or                                                                                                                                                        | AE adnrinister                                                  |                                                                                 |
| ?                                                                                                                                                                                                                                                                                                                                                                                                                                             | cofiicosteroids                                                                                                                                                   |                                                                 |                                                                                 |
| 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). |                                                                                                                                                                   |                                                                 |                                                                                 |  
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.
untitled h1
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.  
  
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.
untitled h1
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.
untitled h1
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   | D")'               | of       | startirtg   |
|---------------------------|--------------------|----------|-------------|
| START of                  | Pembrolizttmal:    |          |             |
| PET.{BROLIZU\IAts         | peurLrroliztutral: | Regirnen |             |
| Dose                      | -l                 |          |             |
| 2-6 WEEKS AFTER           | Da1'56-8.1         | 100 utg  |             |
| C:RT                      | 3'*:5u ?00 mg      |          |             |
| 2.6 WEEKS ATTER           | Da1'56-8:l         |          |             |
| CRT                       | I                  |          |             |
| Q3WEEKS                   |                    |          |             |  
  
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         | Da1'18   | 100 mg   |    |
|---------------------------|----------|----------|----|
| END OF CRT                | 1        |          |    |
| Q3\\TEKS                  |          |          |    |
| 2 WEEKS BEFORE END OF CRT | Day ?S   | 200 ttig | -) |
| Q3WEEKS 100 utg           | 4        |          |    |
| AT START OT'CRT           | Day 0    | Q3WEEKS  |    |
| Af starl of C'RT          | Drt"l- 0 | 200 utg  | 5  |
| Q3WEEKS                   |          |          |    |  
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,
untitled h1
5.5 concomitnnt l.'ietlications/vccinations (allorved &

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.
untitled h1
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.
untitled h1
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.
untitled h1
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).
untitled h1
5.5.1.3 tcchnicl 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.
untitled h1
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.
untitled h1
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).
untitled h1
5.5. 1.6 trrget 'olumes/n'iotion l{rnagement

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.  
  
  
* 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.
untitled h1
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.
untitled h1
uorlzlllqoutul'uoprlnuls i i'i's's ri.iolfu{ ltllluq)el

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$utrutll nolloul Y
'pa:rnba.r 13 Stnrnruld ;uauqua:1;o ed& aterldo'tt{du aql pru artbttqral luatrrafurruru rrprlour arll alilltualaP ol sluallutt 11u tlt-r paturcr3'rad aq lsl[tl ]{Ialltssassu uol]oF{
uoIluFrmlS
.i(lutsrpprru..lllu.ratulspla$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 -
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':*;
'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  
  
.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,
'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
'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{
'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{
'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 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
untitled h1
uoprau!la6 iuotruuy iburjo1{ pur'uoqraullsq leajsi'suollrugag

'setpus Sttt8utul.Iaqlo pttu l1d uo pasuq,trussararr pauraap su perlrporrr prru 'JJ Sunnruld asuqc{ al8ms aqt IIo peluJtsuotuep $u as*aslp sso.rd ulrorn{ Ilu sr eunrloA.roulrq sso.rp :AIO r rorlmrleq 1a8"ru1
(,no1at1aas-struf,s pJorl rpuaJq I uo sr\Jl) a(JlJo rro[ilt arl]
sl A.t1;l 'pa$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$sua]ur
[IntrIIxu[I uo {1tla.rp pa:noluoo errtrlloA.rorrrnl sso.d arp "ro'seiunn pJ]r]Ja.Lroo,,iro1audsa.r JItt tIo s.,\fD a{ll lo IIoIul} eq}sl tlJlrlAruorlour .rourru .rlr.; rud.ruru sulcl .119 :.\JDl I
'1-Igeq 'srr$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 -
Ierr1nln l11a.LnIO Atttlru,ralr{ oqt ot $urp"roocu 'tstEol6}tto uollslpu't 6ut]ea:l:q} '{q 'iruoluuu i.rri"iiua *l grnprocos palrya puu pa,t\al\e.r aq II*r armrlo.\ sq1 'sasuqd.(lolu.ttdsal lu ttt s,\L) 11u furtrrquror,{q (g) r(} :aroq.Io'}.IusI['strfuqdosa aql sB t1:rtts 'suu8'to paA]oAulml OltI
furpualxa lnoqtrA\ asuasrp crclo.rso.rrnu lts.,mll3qlls apnlJul 0l lIIIu s {q j\lDI aIIl SmpuBdxe iq (f t :sdu,tr onr)lo aui) ul paleal: aq '{prtaluunlra-duut i.1I '1111 ,.rI) ItmI g snld ''\-i-C!  
.ro'riorlo.., snld ,g3 aqlJo {Ioltnl aq} sl aunllo,r }aElu} le{uatul unu3+.\Igl:.'\J-I :AJI :
'prtlptlul$ artlruld 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 :
'sutxoqtl pttu sttolo.rd qloq 'IoJ nol|uillur\a ttultl
.IO,I
'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
'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 :  
| -stas ulup nnmutut 0l ) rrurs Cf I 'trurx 6mqtua:t1aary 1                                               | dmlsa                                     |       |
|---------------------------------------------------------------------------------------------------------|-------------------------------------------|-------|
| a'uqluarq aa.q tlllA\ uotll:llltllls 1) C-r                                                             |                                           |       |
| !lGl!FF!!lF.tt1 IllBa Iu pa.nlt)ln0l sr\IC II0IIIIl                                                     | (qooq                                     |       |
| -0F 'ii a) sasuq{i u{) -urBaq aql JC, $AY                                                               |                                           |       |
| j\Id={IruIS+.\II ,111=(uuug -s) AJ"J+ttol 'j\I9I=tt0Ilour JOllnu snlcl rotrrnl ssor6 alu.raua$ oI Pa$ll |                                           |       |
| sasuqd IIUJo sA-I.S aqlJ0 uolml.I0 dI!\                                                                 | rasutlrl IItsJo CAY                       |       |
| palBJrur;                                                                                               |                                           |       |
| iq 0l aJE SJnOluo]                                                                                      | u0llslnf,lEf, Jsop                        |       |
| orunlor ya8ruS lq1                                                                                      | JoJ pasn aq ol un)t                       | suu)s |
| rlltq.tr uor; saErtul                                                                                   | (sgas utup Etudurut                       |       |
| 61) nurx (lt I 'Iltirs                                                                                  | futqlualtl ee.q qlllr u0tlulnulls f) Q-t' |       |
| Eurqtualq aal; 1                                                                                        | luaruaEuurtrq uolfolt                     |       |
| lll 0aIII)a(15 su s0l.tutr<                                                                             |                                           |       |
| lr\Olaq elqul atll                                                                                      |                                           |       |  
| .,\1d,={rrui-t+r\Ii ,111=(nrutg -$) Ar.)+;\rgl ATCI: rr8)s plog qlusrq Il)Ba le pa.nlol[o:)   | u0Ilelllf,lllil as0p    |                   |       |
|-----------------------------------------------------------------------------------------------|-------------------------|-------------------|-------|
| sAtDJo uorut}                                                                                 | .r0J tlts)s auo lf,alas | 'plctq qlBarq aql | (.:sv |
| lll0qll.\l.ro qlun) ploll IIlsa.Iq qlu\                                                       |                         |                   |       |
| rr0rlBllrlilIs 1l c-f                                                                         |                         |                   |       |
| .1o ;trpql:rnPo.rda.r ssesse t)l sat{Ill I ul]:]s pJorl qlca"rq luadag                        |                         |                   |       |
| Ajd:rmuS+r.\J.l 111=(unug -g) Ar.)+,'usl .\IDI= (o..;gg-gtr id'a)                             |                         |                   |       |
| E0 eq III"I\ muaq aql                                                                         |                         |                   |       |  
'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 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  
  
.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
uIJalLI.) aruur ldttroS ptrll sl{ilu.Ilsoo ) a$oq a.Ilu }trl}q I 83I1I.I.)  
| %0f .r SF;\                                          | 9'o! [ 0,60i " St,\ r og,r                                | l^ulJH                |                            |
|------------------------------------------------------|-----------------------------------------------------------|-----------------------|----------------------------|
| qoig ;0t.\                                           |                                                           |                       |                            |
| rr gQ't) ,:" IiJ                                     | .rr t{)'0 j.QtA                                           | **Pr0.) Iulrds        |                            |
| )3 S'0.r; SIA J) 0'l \ tlj\ r1r 0'[ -" 0l;\          | *ssuYaid lBItl)lr.Ig                                      |                       |                            |
| aJ[a.IaJrmr].II)                                     |                                                           |                       |                            |
| lurpudSt: :lr 5'1                                    | aJuaJa1{IlrJrtl 1ut1.tud 3o m 1 ; (Ig"U),tn ft :asop xn}{ | snfuqdos3             |                            |
| ; (AffU) iC ft :esop xuI.\l 9.6tg - g,1arm1 :(Ag$ nC | -                                                         | dtFa[ firnr1 :(Tfft{) | (,11O srlult(I E{Iltl ilel |
| iC Oe - C-II{ :ool t ; 6iA                           |                                                           |                       |                            |
| ir , c-II\i.ro o.os[ ; 0t,\                          | + iull tqiir.r) Eunl luuttoN                              |                       |                            |
| cr !'0; StA                                          |                                                           |                       |                            |
| * orll]ldaslY tloIluI.Illj\                          | It]3o]o^rd.Iad                                            |                       |                            |  
'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 *
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
'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
'{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
'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 -
{ir'imrs 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$l .Io ,\1D a{} 1I lla;ta perllpal aq io{I
prliCIrrs Lffi;;;3i;;,;- ,lq1:.nuqon *r y_*1i, y]Tlllllf"::.:'\t?jll"::::11,1,:IH
!')tlri,.j;)ii;ffi r,i,*ffi.,li; i,d; .{eru .11e aql q;i.oqf rra^r :a}orr 1uu1r,rtlru1l
'pelu3l, eq plnotls j\fd Arau u plru 'ur6.rcm + AICiAfoLrAau atl] o] palsnlpu *q prlolri j\lJ aq] asB) srq] q
'surloJep lo..{ruoluuu.Iaqlo o} e'\Ilqar sglqs AL5l aql;t ilussaf,au aq oslu Kuru fumrolrroca1
.amus aql rrruular pltloll$ 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
'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 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 ' 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
'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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stuorg eranpy tduaql uollrlprll 6i'i's's

'..r-nr[nr Eunl rtgctuoldttr;(s 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
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sqrbtqdosg 0z'i'!"s

'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$uqdosS
'.nloclqul '.lg ,gr1ou asuald 'luaAa slqt uI 'palclru:a1tn luetulua-Il raql a,ruq duru srllBeqt{ose fo s,$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
'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 UO dup b 96 fiu 00i alozerro:ro1a; (1 sp;Srqdosg uoltr!pBU go luauraEuuu6 rrorlulpurfo uollaldruof, aql Itlmt,iup b 64 8ru 961 alozutrocnlS (1 sp.rBprrBls lBuortru{snr.Iad sB qsB,\rq}noru 316BI{ (t  
  
  
  
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
'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
untitled h1
uollbrlslulrupyrduraqlotuaqj lue.irn)uo} ii'i's's

'(s.{uprloq Iuuollur lerluagod o} atlp iupl -,,+) 9S pIru "6i.'tt '! t '8 'l s:(uq :.{clu.laqlory€l 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)
untitled h1
asop uglrltloqrr) iu'i'g's

[(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
(tpi6ttt)
a$rilleal.) ttrllas x el,,(,{luo salunra;) 58'0 x (8:1 ur 1t1Era,t lurqly) {a;iu-6p1) = (trrm;1tu) t;t:
:'urtu,.-Jul sII paalxa lotl pltloqs ptru (*ro1aq) uollurrba llnu9{o.r{3o) aql6ursu patrupl;}lur aq plnoqs I.}.I) aql
'ssa[ aq ,{urn 1l lllrl .unui.Iru 0S I x (Trrr.,,rntu x 6ur) )ny la6.nrt peesxa lor pflolls asop trrlulcloq.ruJ ulllturxBrl arll'a.rofa.rarl1 'unrr,,Jnr 0SI x (1ur,iEtu x fru)^1ny le6rul:(fltl) asop ur1u1cloq.ru3 t{Illtrlxl}}{
asop urlu1<Ioqiur eql Jo rrorltsltrlluca.r I l{rB.LIr}Ar 11trrr 'aluu.rual.! eturll}8a.I} pelull}luJ
,(1:1aar.r tlo pa$Bq 'errr{u}BaJc ruruas aq1 u afuurlJ o.bgI< t} '$esop iplaailr ytattbasqus Jo{ :aloN
'penl aq os1u.,{uru uollf,elloll etllrl rloll te ts ulor1 I.)"r) ps.mseattt Y
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m!l6jlslultupy idrraqloruaq)cz'i's's

sJIlaltlelllru p.IE)truls IJIIA\ saltllmrl 0f
-raAo laxgtrpud aqt ragu ua,rrf aq lJl^\ urlaldoq.rur atll 'laxBllllud o1 .tot.ld salrttltlll 0[ lsBal fB
(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 po.ratsltumpe iq pploqs r(elulatlloutaq-r ';(uplloq ts u0 sllBf ,rclulaq]oruaqr 1o ,rup aqt 31
'tuafiuua.rlJil r(up aqt uo.{clu.raqt uorlr]rpu.r aq} o}lotld pelarllap aq pplotls {du.ratllr:rueq-1aqJ.  
  
  
'uertrs,{qcl Egrlua.rl eqtJo IIOI}a.IJsIp aql l8 sI lololold3;o }$aln}Ba'rl Jaq}IIU '1oco1old aql ffi pegriacls su arlurl{r{)lllr,t {ror}}alloJ ts}t}p pue citt rt\ollol 'pellul}uoi}slp aq plnolls luerrlgaJl 1oco1o.rd 'sdup g { uuql .laEuol "rcr.tr parnba.r eJu s{uarq luetlll8al} lI 'peluafinl:]op aq IIIA\ 1ttq drr apuw aq lorr llrrril ,(clu.laqt uonurpts.I qlt$ 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]
6t-gt- 'f E-6i '1T,-ZZ 'dI-SI 'e I-8 'S-l sdug s1aa,n 9lol {aa'\\ 'rad y S '19l 09 uDIluIpuU
9f pue'6[ 'i[ 'il 'g '1 s,(uq e:JilY urlulcloqrul gE plru'6e 'e i'SI '8 '1 siug f,Itt,rf1s 0S laxulll)ud aFlpstl'1s as00 s.IUIIlIllll\ luatulBa-rj lIla.tII]3UOJ
untitled h1
uollslnturod lerrlll)8d iz'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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uollarutlard lsxeliirsd su'i's's

pltlu,{l aqloltll (slrnpo'r6 a.rorll11rtr.1].\c.xallltr\tr : f .a; srltr.trrlll..I.0 tturl].talua.tli lort azrs a'rtrrl  
  
  
' g" irifU .sll,r.rD,{o.6rur -rrpqclo"rpiq u 6'rrturockorm dq patlsrldurr:rru aq plllotls uoqu'I}lt.1 ailll
-uI.srrorltllos 1axu1r1aucll0 rrorf0.Ilsllurupu.IOJ,{.tUssarau sl lIOIluDIli auII-uI'aJOJal3qf {s.artt
.roJ lsal rag'rt.rulnrrt-rud 4511 a{} .(q paqsrlqu}sa slltrq alqulclacru :3ION1 laxuypu<I
: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 Jo llollu:lua3uo) lulllJ u ol tlotlralur s.'rafurA m as{f,'Ilxap q'o! lo 'dsn aplloltlJ ttllllpos 0'66'0
.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$1m IBII arllJo slllslror a{I'o'ir0S"dsn'lorlorlu palulpdqap puu gtOE (1g.ror1cloura.r.1) yo rotsur pelul{q}e.'fxo{1od m (lut.t,fru gg) s1ul.r' IliI E uI Imrdm 9
'altsrrraf,uo; ltorlrrlos allrals V '(J"tt-*9t) J"SZ-*e uaaAuaq pa:ols aq pltloqs sluIA JaxBlrl)ud
.pesp aq lou pfroqs uorlur.ruol .ra$uru aluprctged e^Isselxa frurltqtqxa suorlrllo$ 'i(rrralod Brup lo s$ol eluJrpgr lou seop uorltstluoJ alulnct;rud qfnc,qlff 'dtmrd rolstgur atlf ol lulslp,{uarqtud
untitled h1
uollbrlslu![upy laxblllr8d 9u'i's's

.Juomaqc Errrlrp dlqaa,rr salllurtr 0g .ra^o pa"ralsllrmp8 aq IIIA\ eTII.it{r 0S laxu}Ilaud
untitled h1
sf )ajj3 asre.{py lexblll}bd te'

"rrorl)ueJ llu)ai {rorll}rpu.r :(uor1u-rarpt {1a.rul'ssaluapua} 'tlol]B.ntpffl
,umeqlrila) uorlurllrym'ur61u,{ur';iqiudodurur8lu.np:u 'anirlu3 'tsIredolY :.Iatl}O o strlt.nucl'qsul'furqsrtg
:aruo.4'rud5 rrosrnlCIf-srrCIrlals :(alniu) suotlruar IBI.IuJIInt prru protrul;(qdutry- :,tSla11y .  
BrrIolo3s 8ut1u1ltlturs
.uorsl,r painqq :sq811 iurqsug;o rrorlusras "{qtudoluqdarua
'r(q}ucloluqclaeua crlerlaq's6urrts poom'sarutes'.{q}udolnatr luraqdnad'qalsul) ,Ltosua5 :1u:rt6'r:1o-nia1q o ssoupapua{l1qfr1 'uorsuapad{q 'uotsna;od,(q 'unuqtriq.uu ltslqt} 'Ilp.rur,(pu.tq
.fitr1) uorlc.rBJur l8rp.n Jo.{rn 'urp.rul:(tl)ut ruprarqu}A '{lolq }Iuatl 'sPltml$tl.rr v: :UuaH o sr$olsall orlurlaq'aJnIuJ rrtudaq :lasututldsotld arrrluqlu'lrrqlllllIq 'JdDS 'J"OSS)
slsal ilorlrm{.ra;rrl pasua^rl(n 'srlrloJo.ra}ua rtuaclo.qrtatl ^slltloJ rltua{lf,sl 'sl1rgd,!  
'srlrfu;iruqd'slllsocnru'sIlIlBIIIols "ueg$Blp :irnlmro.t pu.u Baslll?N :lutlllsaluloJlsBC .  
norssarcldusolaitrq :rtEololuruag .
untitled h1
uoltulnturog u1r1doqrtr) 8u'i's'5

'lollrrrgrlr puu urlulcloq.rulf,o lrl8ra.u iq suud luttba stttultloi) Iurl q:tug 'uoISIguI
*r1.1rr"*o.rliu iq uorlu.rtrsrruurpu.re4 urluldoq.rur;o tirtt 0Sf puu':iur gif iittl 95 Sunnuytoa JBr^ asop-alfrrrs u rr alqelrts^u "lapmr:d pazrlqdo{1 alr.lets u su pallclchts st tlrluldr:qru3
untitled h1
uogluludar6 uqrldoqru) 6['i'5's

06 aJrrrs :a:rqu.laclural rsoo.r lu s-nioq lqiila.Iol alquls a.ru slrollnlos ttl1u1tlu.tu6 'pal:ta"rry su pa.luclercl uaq ypu,'ful 0l l0 tIOIllrIUe-llIo'1 tttluleloqlur u a:rttpi-xcl IIU suoUnllp isaql  
  
IlIr SF ur 6m gEp Itil SI q 8ru 951 I(r(mEru0S
aurrloj\ t{raur(I qtEua.ns lul:\
:alllpaqDs dtnarollol arll ol iitttp.toJll,'dsn
.uorleaful apilolqJ rrrnrpos q66'0 Jo 'Jelul\ {II aso.t1xep clot 'dsn 'ttotlralm .IOJ .Ia}uA\ alt.le}s
.rarllre qtr.r$ pelurlsrroJe.r aq lsnrr IBrA rllua Jo tual(IoJ atll 'asll a.Io1eq .(laturparrnnl 'tqfq flto.g pal)alo.rcl puu a.nqu.radma] txoo.I pafio.Iluoc tB pe.lols uaq,n afupud aql uo paluJrpln eJrl arll ^roJ alquts aru trrluldwudf o {ilurn parratloun 'elqultB^u dllutcratrntror st utluldoq^ru3
'uoi$Jlp "IagB slnoq xpta pap:ulsrp aq suolllllos m1u1du.ru6lurll pep$eururoceJ sr lr'uorlulnttuoJ eql nI poulsluol sI eAIlB,LIesald luualruqtluu
untitled h1
rlolttrrtslulrnpy ultrultloqrsi) 0f'i'l'g

(umr,i1ur SU I Tg f'IL& C1,ILO'ITY IJI.MVITJ SNIMUJ I'\iru'{IXW'{)
:aJuu.ruali aurrrrlue.r:r uo pasuq tsFruLIoJ }taAIB) paqlpotrl arlt Smstr 's,,r\olloJ su (iludm log'Eur ur) palupulur sr mgultloq.rulJo asop aql'asop trrluldoqrlrc 3tl]lo lroll8llrslBler I yru.rru1\ Jlr,1l 'ecuu.rualJ arrrrlsalc peluptllluc .,(11aalr tto Pasuq 'atIIlII]B3.I3 lrmla$
aq1 ur aErIuIIt o,t0[{1 *'**sop,{6aaa,r luardrasqns.Ioc .atoN 'Eursop (a,uttl Jap(nl uaru) 3I.Iy aq| puB lrsr.,r luarr$8a.rl rlsua 1u lr1fla*r,{poq 1un1ru s,.yrattrud eql rC' pesuq pe}ulllf,lB5 aq l[r!t esop arlf .saln{rur Q! .re,ro uorsluur /1 lrp sB laxu}IFud .ragu pe.IatsltmuPu eq IIIi,YI urluldoqlu3
' (;(clureqt trorl uPtlclsuoe)
9:)l Iy .rr: ({clu.raqt lue.rmeuoa) Z=)fiy sr }uaruua.Il urtrulcloqlu;r rq} Ji'}V ta8rul* st11
- (gf l aJrlu.rualr auruIlBar.))x xJ1Y 1aE'ru1= ssop )nV
ur aurmlue.rs ruluas x rt i(E{ ur lq8ta,Yr) x (afu-gtr1) x s8'0= (ulul.-Iul) I.).I.) :sslBIIIaJ 'IoJ
lpiirrr III aururlss.rc uruss x u\#(E{ m 1t161a*l) x (adu-6y1) = (tuut;1ut) I.:.t,: :saluul.IoJ
: BlntruoJ llllBC-U o.qlo J arl] 6ursn' arrtrulua.I J Imuas uo paseq 'palwllltse aq lllit asop urtuJrloq.Iur aq] alsprlu; clt pasn altluJuali emrlluaJs eql 1p7iut
untitled h1
turag esrejtpy uprltloqruf if't's't

rloll]i]a.I rrii.rallu'arrftlu;'ulr'1u,irn'nltctxo1o19 :raqlp t sa:i'uuqr Julil3o'iqludoruatr 1u.raqdr"ra6 : lultdolo'nra5,1' u mraclulxaddq : unttasatrf unrodirl
:aeiltspqmr aflo.r1ra1a :,tlrtrxol otludatl :Btulnuo,r ptIB tsasrrufi :lurl]sa]troIlsB0 .  
ur:tssalcldttsolaitrq :rdo1o1uma11 o
untitled h1
suollbrurpolt aso(i et'i'5's {ae 9

r!)sroql Eur.rnp {14ae,q dlsnoua,turlq (I-)i}Y) u;luldoqrsJ puu (1tu78tu gg) 1lxrl;1rutr
'sa1r,l':r Ilorlslptliolnaqr luanbasqtrs m paArollu sr rrorlults)sa-e.r orr '{.I0llulpuJotuaqr iulntp pa.ltnbar sI uollJt}pe^I asCIpJI
.:(clelaql lua"LmJrroJtro rrorlB.rnp aIIl Jol "illrrattuuuad pl"rl eq fll/lt sErup eqt 's{aa*r anIltl)ssfl0) Z twtl} raluar8 'IOJ plsq a'ru urlulrfoq'rur 'Io ipuu 1axu1qcud.i1  
  
| I = )tlY                                                       | z                 | 0r   | [-   |
|----------------------------------------------------------------|-------------------|------|------|
| I = ltlY                                                       | SruTEtu gg        | 0    |      |
| Iara'I ,so(                                                    |                   |      |      |
| utlrldoq;n.;                                                   | IrlxlIIltrd       | aqr  |      |
| I- {aAaJ.{,ioloq {IOIl.}npaJ aiiop ou a("lllIl\ a.rarlJ 'asutl | r0riulpuJot rarlf |      |      |
| sun7[rronr?mraJotrtal                                          |                   |      |      |  
r0riulpuJot  
8ut,uo11ctj  
rarlf  
aqr I- {aAaJ.{,ioloq {IOIl.}npaJ aiiop ou a("lllIl\ a.rarlJ 'asutl  
)uarn1.r{Io"r aq} q}oq Sttltttp sttol]uf,$Iporu asop 'rol pasll aru sla.\al ostlp  
'.uroqquf 'Io li,ulro) 'l3trli000'00 | > |alalBld 'Io IlflIi 00s'I
> )lW s8rup EmploqIo s{aa/r g.ra*u JI'lrlul000'001,- s1a1a1e1d put} 00S'l { JNV ol lalof,al slullo),r"q* 1g,x1.r,pr", "tup o,i1*sop sttolta.ttl;e {du:atp allnlla'I ptru trp1ea'tr:t3etlJ*
'l3uv00$.1 )NY'eqt u3II.t\ peuulsa'I aq '(uru iduraqtr $orlBrpur
:(1cr.1ggE )" )NV) emado.qnau lo.l plaq sr dclularlt uollslpuU '(1aaa1 asoP I-) asop stlot'ta'td aql fe 1"""fipu.t Jo gollgrllillrlo3 ll-lq 'urlu1doq.ruc Jo gollsllurllroJslp uI llllsar III'\\ uotlslpu'Io11leqc iumrp lort.r*par asr:p alrclsap riirrurrjro tt,tailo.rtrn., slI.IqaJ I- ,(q la,\al a$oP laxutr'r:d pttu
.rr1"1doqlo, aqltro asue.Iiap u rll lplsal ilt*r uorlulptsJorrtaq:r Eulnrp Etlurttcro uruatlorlrra[ olpqaJ
'o,b0l -{: dq saduuqr asop pe}tsloJlt}l eqt ssefm rnluldoqrurJo ssop aql a8wqr o1 ,(russarau lou sI lI 'f,lretxol llrual lOJ sltollullllpo{u asop oll alu alalll :"l1tl}txol IBIIaU :
(1u.raqclua6) :$t:rtxo1o.me61 :  
| -ptoH           | lcurl000'00|. "                                     | ro I            | l3url009'l  '                |
|-----------------|-----------------------------------------------------|-----------------|------------------------------|
| esop snol^eld   |                                                     |                 |                              |
| 1n^             | anulluoS                                            | tcur/000'00 t < |                              |
| esoG laxElllrEd |                                                     |                 |                              |
| puE urlegdoqle3 | lalalBld                                            | 3NV             |                              |
| DT              | t0Ill I                                             | t{aJJilJtlt}    | t.t il p ut) t I D ) rytpQl\ |
| tl.)il.         | a tau                                               |                 |                              |
| /J              | ilp ut)tID)Ury)Ql\ atau i1r.'rr xo1 ctf o1 otuutall |                 |                              |  
'uquldoq-rur glltr lttatrrlBar ali{Illuot lllq'Iexu}lllud anmluor*lp
.sKup 1I < .ro3 ple{l sr Jaxulrpucl ;1 'nrtuldoq.rul qll^\ lnauq8a.I} alrurl{Io,) 'uc}l}.'}rlpal leAal asop aro qlt.n amnsal rraql '1 apu^r8 ; ol sa.,rl$sa:r iltltxolcrrrlau lllml 1axulr1.rud ploH :I "i \pD'tS
'esop IIlu lB lexBlllru(l entg '.1 apurD
'sluatlud .IePlo Ifi ;tllulcadsa palutlllrAs 3q ol paau ieur s1a;ra1 f, I8 rrlt$t?ll^ pIIu alBlof, :p3{raIIJ 3q pFloIIs sla^el unurluc ptIB
irmrsarr8uur ..n.ing -(,uo1aq aas) ,{1trrxo1 ctEolo"ntau .lo] pal]IPoIr ]('l pltlolls sasop laxullJ]Ed
:illllxol illludaH I  
  
  
:nrro Iaxulrlsud.Iol i^esop fllli\\olloJ ;ql a,\I9  
  
| x,PI0H                   | IP.IEIU i'I   | lilrs'-   | fi.'il*]" xS.;   |
|--------------------------|---------------|-----------|------------------|
| la,rel esop I esua.lJa(i | lP:nttt g'1   | p{\       | N-In x 0's-s'r   |
| Ia,\al asoP aluus        | Ip,,6wr t'1.> | pr\.      | N'lII x! (r. ISY |
| Iaxulll:)ud              | rrrq[rIlIg    |           |                  |  
(m;ulcloq.rua qlur lueulluall enurluoi) r(clu"raqt laxulllrucl artutluolslp's{up Ie <.rog plaq sl laxutrrlrecI;I 'qluldoq"r€o qllAl luaffil?arl atruluo;) "Ial\ol Ialal asop e$o lu luer111ge{ ".,o,*r, rraqi 'pi6ur S'l .}, ulqtul11q p$u NTn x S > JStr ll]ml Iaxullllud p1o11* rnluleloq^ru; ol,Qt,ultsuasrad"(g :
',iduraqt y>aolo.rd [B Irro.IJ pe,\'ouleJ Jq pllloql l{lallud :f 'to t dpt};9
'ur1u1tloq.rr::r Jo siasop luattb*sqns IIU aloJaq lua:1ard puu ellosal stttolrluds ttaq.,t\ tltlulriuq.rn" 1*1t"U 'se{Illaplli8 1uuot1tt1t1s(tlillol]a'If,srp uurils'{qd o1 Srrrpiorce 'auosurllarrruxep -/+ s.Ia:polq f,H ro,/puu IH.IalslunupY 'uotslUm aqt dots 'e aPD'tt
'a1u.r pamrqd lurlryl arll lc uorslqrrr arll [B]sa.I ueq] 'aAIosaJ suroldtnds lll{ni uolslUul slll Arols :I aPuJ1 IaxBlIILd rlt iltatltsuasraddll I
'1axu1r1:rud qlr* {dtllatll snullno:}src;:f .to t apilr9
'sasop luanbasqns II8 eJolaq lua:lalcl pIIu a,\lose.I sriloldtrr,{s uegll LIB}seU'sauqapulf luuotlnlqsul]tlol}e'I}stp uur'-lrs'{qcl o1 Etrrp.rosu auosuqlamuxap -l+ s.Ia{eolq ZH.Ioipuu IH 'Ia}sfirlulpy 'tlolstqur atp dolg :{ aPDJg
'alur Pamtuld I*rlrr{ aql }o uorsrytlr arl] l.rulser uaql 'aAlo$a-r suroldmds lr]ml uoIslrJUI elll it\nls :{ apo't9 IaAal asop auo qlr,\\ laxulqru<l puu ulluldoq.rui atmlsa.I ptfi) $sa[ Jo i apura. ot pe^lose'I
aA?q sartrorxol aql 1t,,ni urluiaoq,n. poo laxelqtut{ p*q '(urxaloue p{IB arl8rlu-1 -8nr1mroa
.orilru,,'uiradc,lu fdacxa) ;J epu.rf paalxl luril $elllrlxol pelBleu-luat1llsaJf 'IsIIlO IIV .  
'rr()r)f,lrpe.r
'palalfttloc sr dduraql uorlBrpuJ srr 8tlol sts ltsr.rl lu]rurlJ sltll uo arlulltlo) ,(u[r stra!-Qlls 'pelrutluosslp aq lsnur .{tlu.rat1}omaqt puu 'o,""oirr1n1.ioq*i ro ijxulqrucl o} pelulel sal}If,Ixol alqutdarcumt;1  
  
  
  
suortrs)IprI\ lut!lltuoJu0.) prl!tlltlord I's's
:lurt sqlJo (asdu1a.r asuodsa: alaldmoa-1sod ro3 treuque.na.I Surpupur) aseqd tuatuluell puu Eruuea.rrs a{lt Eumrp sardu"reql Eur",rlo11o; etp 8uratale.I mo.q patrqqord a.tu slcalqn5 10:lr:};rd sl{ll trr parlrads 10u idu-tatltountrmlJ .  
locr:1o.rc[ srq] w pagroads 1ou {du.taqtoulaqJ .  
'a{rrlJu.\ ploqd,q puu 'DJg 'sorqu.r '.raial Atolled 'lalsoziu11eJuu.r 'BIIaqil "srluttrut 'salsuaul :a'ur,tto11o1 aql'ol patlql lou a.ru lltq'aprUtrrr sarrrf,ruA olrlJo seldutexg 'lulll oq] ttt itttludt,rlg.tud epq,lil puu luefir]tseJl lur.r] Jo asop ls4] eq] ol .rorld s,iup 0[ IIIIUT^\ satIIJ)t]^ a.{.IT .  
quunzlloJqurad ueql :aqlr: sluafu letlr-'rrluftlsa,rul .  
',{russacarr d11u:rrpaur aq o} suraap "ro}BBr}salur eql }BIII s(Iolluitpatrl JaII]o a,ttere.l,{uru slralqng 'luLrl aql ruo.r1 paAoura.r aq pluolls;traulafutnlur [u]ruII).Ir]tr ril{IaIItlua.! pauoqualueroJu aq| Jo drru yt-r osn aql amba.r ':olu8rlsa,rur aqt .{q luetllssassu aql uI 'ot1.,lr stcalqnS
'.rr:suocl5 erll {llm\ uor}u}p$uo.l.ragu pa.,ro.rddu aq iuur splo.IalsoJI}.IoJlo sasop rr8olors;(qd.Io asrl aq1 ',{Soloqa rrfolomlurur patJadstts 1o lsa.Ialut luf,rIIIIi Jo luaAa uu ruor1 strroldrn.d.s aluluportr o[ ue{il rarllr:r asodntd duu .to1 splo)I}"Io"ro:rtt1f rrrtrals.,{5 o
'luul srql u patrqrqoJcl a.ru qcq,u suorlu)rpanl Jaqlr) saqr.Ilsap uI"IelI.rJ uol$Illrxg eql
'asuqd clu-*ro11og lrraurlua.rf-lsod aql:irrr-urp satdr:.tatJl palqlrp.xl o(I a-Iu a"reILL
untitled h1
ajb) atluoddng 4y uollu)tpel anlsill

' qrxilllzrlo.rqlrrad 0l palBlar aQ of ;:-fuar\a arll siamflilatap ^rotl]iirlsarflI aq] ueII,\1 pallddu eq ol papualllt a,r0 sauqeptltS  
  
  
tuamtuall arLL 'eJBc a,lrpoddns lu{rorlrppu a.mlbal }qfnn IIJITI^\ 'III}I}IaJIII IB.IIr. Jo IuIJatJuq
.r0 osuasrp irlulsBlaru su llins sa$nut.r0qlo lno arlr o) apuru aq pll}otls stdmall8 'JlpIosry qlue JOC 'pasBa.rJep sr asop proJals a{l} {raq,{l uas.ro/r\ .ruur srnoldruls su irussacau 3q {B(tt Etrnadut prorals Jo s3s-moJ lu.reAas turlt 3"loN 'spro.relsocll.I()s Jo lIoIluIsIIfitIIpu qlri!\ alo.ldrtu lott i:p stuoltlnris 1r struaEu r(roluunuug{rr-l}uu [uttoltrypu su IlaA\ su splo.Ielso)l].Iof, t[lIA\ lilauqua.I]
sliorra,\u.l1rn.ro IB.rofo asn eql aplllf,rn sauqaptni asaq]'alultdolddu a.rattr11 'l{Iatlll}Jop a:ruupttrf I )A a{ll rrr lrulep.raluarE ur pilu ,uolaq parrllno a:u i6o1or1a rtiolotmrrmtt 1ut1ua1od {llllrt sfnala as.raj\pu go ltraruadumlru arll .ro.I sa.rnsuerrr a-IBJ a,rrpoddus palsa8in5 ':olu8t]sarrtr Euluall aql {q ,(russalau peuraap sl} sa.rnsuaru a-Tuo a,rr}rodrhts a}ur.rdo.ttk{u aJIeJa.I Pltroqs slcalqrr5
'IIoIlBs$IpO[r asop rol I-f,'E rrorl:)as cll .raJag'(luauurcop aeneplnd 133 arll trt patrlltlo su) aruuprnf
]uauqua-q aql i\tolloJ tll Paeu lon saclP lnq a)uBpnt6 dutltoda.l Il3 aql .t\olloJ ol palc{Lll$ul sr .rolufrlseAm eql 'palular aq ol lou peumuetep sI luaAa aql tlollutllu.,\a eql JaIB JI :aloN
'luaulutop aruupttti 1.13 ar! tfi ptnlo; aq ru]'aluudo.tddu su 'sa"rllpaco.rcl luuorlrpuor palsa86ns 'iuaAa aqt Jo llolluulu,ra Jo t-IBd su .l,qdurdoloqd uqs Jo 'idocsopua 'ddoisorl;luoJq su qlns sanlpaioJd IBIIotltpuoJ mIoJJad ol rllussa)au aq .{Btu lI
'(srrap puu su6ls luauo]l.Iad su qrns) {Ior}B.Iol.lad la^toq J.J prlu (:aaatr )noqll^{ Io tllll\ 'loo}s m sllJlltu Jo poolq 'mucl luttturopqB 'ueq'ilulp sB
ipis; srlrloJo.Ialua go sruoldrur(s ptru sufts .IoJ Perollll.rul dlllga'Iur aq pltlotls slrahils
:$!lllo.)/stqJr8l( .  
^ s{aa-lt\ t' trtllll ssal oILIi;\t) pilllll]Iloit radul plorals'ssallo I apuJ{) ol a,\o.IdlIII stllot(klr"\s tlall'\\ i:)
'sploJats I8r0 esop q6tq iq p3,\\ctlloJ sPlo'Ials
'-Iaa.,!r | ":. slsrs.ricl lHll sllllor/uaqrJrlp r ro e tpurc .IoJ i-t
'spr0Jels0JIlro:)
prru paluls aq Plllolls SIlt)UaAIr.llm IIII!{I\ } 8a.I}
lu.ro "ralsrufirrpe
.sdep g rrug.laluals slsrs:ad lurll sllllollBaq.I.IBlp z ap$rs .10:J ,-t
.srlrlo, lno aFLr.ro uullrrof, o1 ,(dorsopua ptru uorlBllrrsu{)f, Is JopIsIIoJ 'Eaq.uulp
"r"qau .Io I apuro .IoJ '{Iol.$rym iu ulA pa}nll'lsqns aq plioqs sadlo'urale pu8 pm$ .elqrsual lQrr st a{ulul pltlti luro luarrgJns JJ 'splnu .Iu3l} Jo sal}I}uulb Iu.rsqrl {rmp ol pasr^ps 0q plioqs sr}rlocruarlrrBrp e)ualledxa oq,tr sl:}alqlts IIY ii,
(f,XC) slsoplrr
)rloqBlaru ro (upnuofa4) )^ltota{ q};.rt pal$lrosss Jt 'ulurar.llB.radig S rprr, <
r; (tr.ff(l slsopl)Bolo{ rllaqulp Eu;pnpu1 '1asuo ,nau 31} snllfieru s'laqclp 1 erlrl lillumrrlola:{ .IO SIs0pIlu  
  
  
illoquterr q]I..r pa]ul]ossu urttlaf,,(l8radi(q F-t apB-I$ .IOl puu slulllaru seleqprp I arLU 10; pepueunllosal st ,{duletlt lgautaruldal ur1llsul r umles{lf.Ie*iH t-f ,ptrr{) io ItOII "toi ilr
'rroq8jtsrlnlllpu plo"rels pa8tlolo.Id lo asui aq] UI srrorlcaJtn rusrrnuloddo rol scrlolqrluts 3rl1u[{{ld0.Id P}rv 1-:
'pepaarr slr'so.nlsBaur {.ro}Br$rrr8[Im-Ilur3 ICItlolllppt IslsltIIlrIpY
'splo.Ials sllouanP.Il[Il tl]t,t\ ]l]3.I1 dlalUtpaunul 'stue,ta f-g apEJ'5 .toj i:]
'slea^\ r uu{l} ssel otr
.ra.{o parttrl}uoJ p{Iu Peputs eq pp}oqs Jadul plo.Iels 'ssal .Io J aPuJC o1 a'ro.rtlurl smoldru{s rrarl\! 'spIoJe]soJI[oJ Jlulals.(s q]tr't lua.I] 'sluala Z epEJS .IoJ *
:srlluounaud .  
' aprlclad-3 pue'urqo J$otttaq paltrlisi: r,i18'ssuolal aurJtl "larlud JIIOqBtam I Ptlu asorlllf tulues qll.'ll sluallud alunlu.lS
untitled h1
srlrstqtlotllll

'palaelul st e$op prolals e{ll sr? pa:rrrbar eq Auut salrottllotl a1r:t.ldo.rcldu.;o lur,,rrruida5 .s{aaA\ t rrgq1 ssel ou laAo perrmpof, prru pa]"ruls acl pprotls .raclr:t pro.rols 'ssel Jo I apBID ol aaoldtttt suroldnds tleqi\ 'sploJalsoJl;ror 1u.lo iq pa^\ollo.l spl0Jalsof,Il"Io.r AJ l0 asop IuItffiI IIB rlllrl\ lue.Il 'sluane ft aprJf) JoJ il'
'pe.radu1 sI ast)p plorals aql sB pa.nnbal aq (etu sauouiloq alurrclo.ltldr: lo llrartraruld;ry s1aa,u 1' rtsql ssal ou .raAo paurrrlno) purl palrulr eq pluolls .raclul pto.la1s 'ssel .I0 J epuJD
ol a,ro:dlur surolclmds IIaIL.lyspI0.rels0]Il.IoJ qlIA\ lBa.U 'slue.\e Z epcJ3 :oJ i-'
's.Iep.rosIp pro.l{qtlo srtto1drrrds prru snfrs lusrrull.ro] pult (ttotluttlusa luJIIIIlil llo pesuq pelu)Ipul i* p,* :1,rr,rr1orr1 6urrup ,{llurqrouatl '}{Iem}BaI} Jo 1tu}s aIIl }ll) tIOII)tnq pto.Iitql UI
safiruqr lo3 slgarlu{.rolmo},{ 'l$aur1ua1 i3'ump aun} ,{uu lu.nl}}o IIul s.Iap.Iosrp pro.r,(q1
:ruslplo.liqlodig ro tuslp!or,{q1rad,{g
'paladul sI asop proJals aql su pa.mlba.r aq {u[r sauc]uuoq aluudr,xddu 1o luautaluldax
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| uondruntm uorrlgrl :uotttsJ., pf hl iTES                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                  |                      |
| Jolu;usr.lm aqt  "1o  uomrdr: ,rp u Jlqus                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                  |                      |
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untitled h1
uortsraprsuo) .raqlot{11.rt1ry71a1g t' teto i't's

'frrrtrruo.r .ro uesnuu 'uaq.uulp st, Ilons Ay rru aEeueur otr pa.nuba: aJu srrorlelrlrporn ssafnl larp ltllluclu u tlltsltltullt plrtoqs slra[qrtg
untitled h1
uo4daruuo1 f'r's

',iduraq ipnlsSo esop tsul arlt :agB sdup OZ t o1 drr 1>onaci ,tpn1r aql proq8rroqt I llsl.1 .(ptqs ttro.rl Io tttlor qttrq frursn ;ru1s plno{ls slcalqug 'druul8a-rd yrana.rcl o} poqterx luuorltoq u sttld po{l}3rl .IeI.tIBq B .Io spoqlam
.Ial.rluq oA\| ia{llra eq tIBi) spoq}am [0.1]ui}3 IIUIq o^U aq"1 ',rpltts aqlJtr tlolltt.Il'tp eIIl JoJ eAl]3u
.{lluuxasolalerl }orr (g .ro '(lusrrudouatulsocl paJaprsuoJ aq gl,\\ .rua,{ 1 ttutll .ta}ua.tf .tol sasuetu pBrl to{r ssq puu afulo s.rua,i g;": sr o{1,,r\ rruruor\\ ei lusuuclouerulsocl (;.Io'pazlll.latrs.{gu,rt8.ms
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.ro IoJt{roJ rl$Jq Jo spoqtaur f asll ol drq111,t a.rc taql lr p.allo.nla aq iurtt tla{roir\ ftrrpaay-lsealq
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{uoprroJ 'rrr8u-nldurp :uorlclalu-r;uor} Jo s?oq}effi .rat.I^Iuq alunllapu pe.Ieplstloi} a:tr fut*to11oJ atlJ  
  
  
  
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.
untitled h1
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.?.:.
untitled h1
5.7.{ lrse in lursing lomen

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.
untitled h1
5.8 subject withdrannl/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  
  
  
  
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
untitled h1
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.
untitled h1
5.8.1 discontinuation of stutly thertpy

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 aclcliticural treittlrrenl rviflt perubroliauna[r via lhe Secr:ncl Cotu'se Pltilse al lhe cliscretiorr of lhe  
  
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.
untitled h1
5.9 subject replacement strategy

A srrbject who cliscoutittues ti'onr the trial will not be replaced.
untitled h1
5.10 clinical criteris for earl-v

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"  
  
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roduct:  Pembrolizumab
rotocol/Amendment No.:  
  
Confidential c o IRB
Expiration RB