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

 
 
Official Title: 
Moving PD-1 Blockade with Pembrolizumab into 
Concurrent Chemoradiation for Locally Advanced Non-
Small Cell Lung Cancer (Multi-Center) 
NCT number: 
NCT02621398 
Document Type:  
Study Protocol and Statistical Analysis study protocol SAP 
2 
Date of the 
Document: 
10/21/21 
 
 

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5l
Protlttct: Peltibrolizittltnb
ProtocolJAtnentltnenl \ o-:
C f;onfid*ntial
?.0 TRIAL PRO('EDI.IRES
7.1 Trial Procedures
The Trial Florv C'harr - Sectiou 6.0 sununarizes the trial procecttues to be pertbnned at eaclt
visit, lndivid*al rrial 1:rocechres are described in detail beiow. It firay be necessary to pel'fonn
these procednres at rurschetltrlecl time points if ileemed clinieally reces$arY by the iuvestigator'
Fruthe,,ore. adclitiolal eyallatiorrs,ttesting rnay be deeuted neces$aly by ttre Spousor and''or
Merck for reaso*s relatecl to subject sateiy. ln soure cflses. such evaluatiouitestirrg firay be
pr:tentiallv sensitive irr natule 1eg.. Hn',. i{epatitis c'. etc.)' and ttrtls local regulations uray
req.ire that aclclitiolal rntbmrecl c,rusent be abtained frour the srrtrject. Irr these cases" such
evahrationsltesting rvill be pertirnnecl irr accorclarrce rt"ith those regttlatiotts'
7.t.1 Administratite Procedures
7.l.l.l lnformed Clonsent
The hnestigator nnrst otrtain r{or-:rur}euted corrseut fi'om eaclt 1:otential srrbject prior to
participating irr a cliuical trirrl.
1 .1.1.1.1 Generul Informeel Clonsent
Consent mrxt be docpureltect i:1.' the subject's ctated signaftrre or by the subiect's legally
acceptable representiltir'e's clntecisignanue oll a consent |onn along rvith the dated signature
of the pel^rion cotducting tlte cotrsent cliscussiott'
A copy of the siglet'l alcl tlateti collsent forui shoulcl be given to tlie strbject before participation
in the trial.
Ttre ipitial ilt'or.tr erl cpuseut tirnu. any subseqtteut revised rvritten infor:iled cortseut tbnn ancl
any written int'or:uatir:l prr:vided t0 tire subject umst receir''e the IRB'trRC's
approvallfavorable opirrion iu aclvance of use. The subiect or hisr'her legally acceptabtre
representative slxrtrld be infrrr:necl ru a timely tnatuler if new intbr:nntion becornes available
tSat r1a.v be rele1,nut tg the sutr.iecl's rvillingness lo corttinrte parlicipation in the trial' The
co,uururicati*n crf rhis intbmraiir:n rvill be plovidecl attrl clocurnertteil via a revisecl cortsent
fogl or atlderrthrru tr-r the ririgruRl consent fonn that captures the snb-iect's clated sigttafttt'e or
by the strbject's legatll. acceptable representative's dated stguattue'
Specifics aboul a tr.ial and the trial populatiou rvill be arlded to tlre conseut tonu tenrplate at
the protocol level.
The intbnnecl consent rvill aclhere to IRBIER(I requireutents. applicable lnivs ail<l regulations
and Sponsot reqrtiremettts.

53
Prodttct: Pertibroliztrttlafi
ProtocoliAlnentltneul So., I' 
O
C 
Confidqntial
7.t.1.2 Inclusion/Exclttsion Criteri*
All ilchrsion aud exclusir.lr criteria lvill be reviewed try the investigator or qtralified designee
to ensrue that the sttir.iect cpralities ft'rr the trial'
7.1.f .3 $Iedical Historr-
A uredical history rvill be obtairred by ttre investigator or qualified desiprree. Iv{edical history
rvill iuclude all active conclitions. ,rrd rrry conclition rliagnosed within ttre prior l0 years tlrat
are co*siclerecl to be clurrcallr, siguit'icaut ty the Investigator. Details regardirrg the- disease for
which the sgbiect las eruollei u, tlri, stucly ivill be recorcled separately attd uot listed as uredical
history.
7.1.1.4 Prior and Cloncomitant \'{edicationr Review
7.1.1.{.1 Prior }Iedications
T1e irrvesrigator or qualified tlesignee will review prior nredication use. irtclrtding arty
protocol-specifieti rvashout requirerueut. ancl record prior rueclication takeil try the sub^iect
ivrttri. lg clays betbre startiug ihe trial. Treatuent lirr the ctisease for rvhich the subject has
enrolled i1 tliis snrcll' rvill be iecordecl separately and not listed as a prior [redication.
7.1.1.4.2 Conconritant Iledications
The irrvestitntor or qualifiecl ciesigrree rvill recorel rrreclicatiorr. if aily' takefl by the subject
clgring the tiial. All uieclicatious related to reportable SAEs arrd ECIs should be recr:rded as
defined il Sectiol 7.1.
?.1.f.5 Diseare Det:rils and Treatments
?.1.1.5.f Disease Details
The irrvestrgator or t}ralitie'cl clesignee rvill obtain 1:rior attd crutet$ details regarding clisease
statlrs.
7.1.1.5.2 Prior Treatment Detrrils
The ilvestigator or rpralilied rlesiguee will revierv all prior cancer treatmeuts iucluding
systernic trea trttettl s - t a cliil t i ott attcl stugeries.
?.1.1.5.S Subsequent Anti-Crncer Therapy Status
The irr,estigi1tor (ll qliililiecltlesis.nee rvill revierv ali netv auti-neoplastic tlrerapy irritiated atier
t5e last close r.rf rnal tieafnrelt. It'a suliecl iniriates R uew atrli-cancet tlrqlry||Ililllll

5,1
lllll$Jj:1li,i:iiTl,r o
C 
Conlidenlint
a{ier the lnst close of tLial tleaturent. the 30 clny Sat'ety Fr:llow*rp visit tuttst occur betbre tlte
frst d,ose of the rrerv therapv. once neiv anri-caucer tirerapy ltas beeu initiated tlie sutrject r'vill
move iuto stuvital follorv-ttp.
7.1.1.6 Assignment of subject stucly ldentificntion Number
A cop.v of
iustiflcation
the utstrhrlron's IRB-approved infurrnlecl colrsent clocutteut and rvrittert
lbr urY changes uratle to the infomrecl consettt tor this
otocol rvill be on hle
at
be
OHRS Registratiorl Desk
Re g i stra tiortiEruollurent
process:
. Registratrou: Au1, subiect that has siguecl the corxent rvill be assigued a urique
patielt st1cl1, grurrtr.r. .Sit. rvill coutaci OHRS and send a copy of the de-identified
colselr. OHRS rvill provicle site with the subject stttdy number. TIte patient will
not be iclentitiecl b\r 11orrr..
En.ollruell: Orrce' eligiSilitl.'has beett confinuecl. the t'otttpletecl' srgued aud dated
eligibilitl, clrecklist will be sent ro OHRS rvittr additir:ual sou[ce documeuts. if
,eq-,,.rr*.1. 6HRS Registration Desk will eru'oll the subiect to the stuciy arrd send a
c,:rrfurlatorr. enrail to the site. This is the poirx thal tlie patient i"s cottsideretl ou
snrdv.
. patients rvill gg,! strrt protocol treatrnent prior to enrollment.
7.1.1.7 Trial clompliance (lleclication/Diet/ActiTitv/other)
Ilternrptiols ti't'.,ru t1c, treillureut 1:lau for:,11, rveeks lretrveetl petubrr:lizuttlab do.ses recltdre
corrs*ltatir-rrr betrveeu lhe irrvesiigatrr and Sponsor attcl rvlitten <li:ctunentaliorr of tlte
c6llafuorative clecisi6u gu t[c- rllflltagertteltt of tlie sltlject.
Aclmirristrati6u of r5e penrbrolizurnab rvill be w'ituesseclby the investigator aud/or trial staff'
The total vohune ol penrtrrolizrunab iufusecl rvill be compareri to ttre total vQhrrne prepalecl tQ
cletentrirte coutpli a t tc e to ea clt close arkn iui sterecl'
i'l ii

55
lff:'.li-T;1t,*ili'$,n
G 
Ctxfidqnlial
7 -1.2 Ctinicnl Procetlures/Assessments
7.1.2.1 Adverse Event (AE) Ilonitoring
The iuvestigator r-rr qualitiecl clesiguee rvill assess each subjecl tr: evaluate t'or potential ner'v or
rvorseni,g AEs as specified in thJrrial Florv chart antl rrore fretluently if clinically.indicatecl'
Adverse experierrces rvill tie gracletl ancl recorded tluoughr:ut the shrd,v ailcl dtrri0g the follorv-
,p periocl accorclius to NC'i CTCAE Versiou 4.0 (see Sectio, I l.?). Toxicities will Lre
characterized in telus rt'garclilrg seriottsnes"l. causaliry' toxicit-v grading' ald actiog taltel with
regard to trial treahttetlt.
For srrdects receiviug tt.eattuent r.vith penrtrroliztuuab all AEs ,cf rurluoivn etiology associatecl
with pernbrolizrunab exposlu'e shoukl be evahmted to deter:niue if it is possibly ail event of
cliDical irterest (E('I) {"'.,i a potefitially inuurmologic etiology (tenned inurruue-related adverse
eveuts. r:r irAEs): see ttre separfit; EC'I guicla*ce rloc,,re*t regarding tle iderrtificatiou'
evaluation arrcl tuattagetnettt of pr:teltiaI irAEs'
please refer to sectiou 7.1 fbr detailecl infomratiou legarelitg tlte assessnteut and recordiug of
AEs.
7.1.2.? Full Ph't'sical Eranr
T[re investigatol ru qualified <lesignee rvill perfonn a complete ptrysical exailr duing the
screeuing period. c'iinicalll, sigrriticarrr abnormal tindings shotrld be recorded as tnedical
history. ,{tiill ph},sical examshoulcl be pertbnned druing screenittEt.
7.1.2.3 Directed Phvsical Exam
For cycles that cll ugr rei1uirc, a tirllphysical exaur per the Trial Flow Charl, the investigator or
qualifieci designee rvill perfcrrur a clirected physical exant as clinically inclicated prir:r to trial
h eatutent achuitttstraticrlt.
1.1.2.4 Yitnl Signs
The ilvestigalrrr or rlralilietl clesigrree will take vital signs al sct'eenittg. prior to the
acl*ri,istratrou of each rlose of trial treatrneut arrcl at ireatrnent eliscontinuatir:u as specitied irr
the Trial Florv Chnrr (Sectiou 6.0). Vilal signs slioulel inclucle temperattue, pulse. respiraloty
rate. pulse oxiuetrl' both *,i,rllmg and r.ri*g, iveight ancl blood pressllte. Height ivill be
rueasured at screettittg ottlr'.
7.1.2.5 Eustern Cooperative oncolog-v Group (ECOG) Performlnce scale
The in'estigator or t}nirtied tlesiguee rvill assess EC'OG stanls (see sectir:rt I l. I ) at scleermg'
prior to thelichninistiatii-,n of eaclitlose ot-trial treatrneilt anrl disct-rntittttatiott of trial fteflil]rellt
as xpecifietl in the l'rill I;lorv ('ltilrl.
*{ }'i

Protluct: Petttbroliztttttnb
PrototoliAtne,rltnettl .l.-o.: f 
' O
C 
Conlid&ntisl
7.1.2.6 Tumot' Im:rging lntl Assessment of Disel*e
Respc,lse assessrpellts rvill be ma<le t^roth using the huuune Relate<l Response C'riteria. and
usilg RECIST r. I " I . allot,ing additiorral comparisr:rrs aruougl.these criteria tbr disease
re$ponse assessuleut. The saiue measruable aud nou-uteasm'al:le lesions will be fr:llowed by
botir MCTST v l. I .t irR('. REC'IST l.l rvill lre usetl ro tietenuine the priurary otrjective of
t1e trial aucl RE('IST L l ancl lnuurure Relatecl Response Criteria rvill be usetl iu secoucla$
objective of PFS.
7.1.2.6.1 fmmune Related Rerponse Criteria:
Tlus sfird-v rvill use tle Iulnuue Relatecl Respouse C riteria (irRC). These response criteria
were clerelc,pecl to ovelconle the r,ariable arrcl rurttsual pattems of respouse tr:
ilurxurotherapeltic ilge.nts. lr) p,lfiicular'. ipiliurtrurab [2a]. The developtttent of the guidelines
were pronrptea U,v otiselr'aliorr-r- ur6sl11, iu patieuls rvilh ntetastatic ntelanotila. of irritial
disease progr^essii',n lbllorvecl b1' later ,:esportse, late responses. and mixed I'e$porrses rvith au
overall dect'ease irt nttrior Lrttrclett.
7.1.2.6.? Antitunror response blsed on total measurable tumor burclen
For the irRC'. onl1.urclex alcl rneasurable nerv lesiorts are takeu iuto accotmt (in contrast to
c.nventi6nal WHO criteria. rvhich clo not require the rnea.surernerrt of ilerv lesiotts. nor dcr
they iucltrcle lerv lesit,u lneasiueulerts ru thgcharacterizaticttt of evolviug ftnilol'trurdeil)' At
the baseline trunot assessnlelrt. the srun of the procltrcts of the two larg,est perpenclicular
diarueters {SPD) ol all ilcles lesious (live lesii:us per olgarr. up to 10 r'isceral lesiorrs) is
calculatecl. At each subiequent tulDor assessment. the SPD of the index lesiorrs ancl of tlerv.
ureasurable lesiops (tqr to 5 uerv lesions per organ. l0 visceral ]esious) are added togethel ttl
prorricle the total nu]lot trulden: Trurror Burden: SPDindex lesious + SPDnerv. uteasuable
lesions.
hetrveen \VH0 t:ritet'ia artd the irRC' criteria
-r(.,
i WHC)
New. meastuatrle lesions (ie
Alrvar,s represeut PD
Ahva-vs represertl PD
Table
Non-inclex lesit,tts
Cliauges cotttritrule to
detinirg BOR of CR, PR.
SD. arrcl PD
Disappearance r:f all lesions
in trvo cr-usecrttive
obserrations not less than 4
SPD of all
>5s5ttutt) 
-___
New. uorutteasruaLrle
ie ": 5x 5 rrun)
Ircotporated rnto tuttrol'
buden
I)r:,ot tletlle p'clgl essloll
trut t:reclrtde irC R
Cloutribute to cletining irC'R
(coruplete disaPPearance
re{ll]ire-iu
Disappearartce of all lesious
in tr,vo consecutive
otrserr,atiots not less tltau 4
,'-50o'o decrease itt trurrol
rvk
retl t ith
1'r I
lr, tr I
..:i"l:i:ii-i.
:... ii,ri 
i
'rlt
I Ll,l
rrr L,
irRC'
CR
IE-

Protltrct: Peuibloltzturtntr
57
Protocol'Atneutltneut ro., f 
. o
C 
ionfidantial
baseline irr hvo otrsetr,atiotts
at lea-rt .1 rvk apart. in
absence ofuew lesiotx or
rnrequivocal progression r:f
ui:n-irrdex lesions
50'Qo clecrease irr SPD
compared rvith baselirre
carurot be established uor
l5oo fucrease cr"rtnpared rvi{t
naclir- iu absence of nerv
lesir:us or rutequir.ocal
progressiort r:f nou'iudex
lesious
.{t least 159'o increase il
SPD cortrpalecl r.vith nadir
aucl or uuequivocal
plc, gression of nou-index
lesious auct.ror a1:1:earartce of
rueu, lesions (at arr-v sirrgle
trlue pornt
7.1.2.6.3 I ime-point response assessment using irRC
Perceutage charrges irr tuuror lrrucleu pel'assessrrerr{ tiure point descritre the size aud growth
kiuetics of both cortr,entioual anclnew. ureasl[able lesions as they appear'. At eac]r tttmot
assessrnent, the respouse in indeii and uerv. nreastu'aLrle lesionr is defined trased on the
chalge iu trunol brucleu latier nrlirrg out irPD). Decreases in ttnttor btuden utust be assessecl
rclative to baseliue nleasurel)]errts (i.e.. tlre SPD of all iniles lesiorts at screening). Tire irRC
rvere clerivecl frour \\rHO criterir ancl. therefbre. the tluesholcls of response reurain the saute.
However. the irRC' response categories lrave treen urodified tr-r:ur tltose of WHO criteria as
detniled.
7.1.2.6.4 Overall response using the irRC
The suu of the 1:rochrcts of cliiirneters at hunor asses$nlent using tlre inunture-related response
criteria (irRC') fil'1:rogressive tlisease iurrorpolates tlte cottlribtttion of nerv tneasurable
lesious. Each rret Pelcerltilg.e C'harrge iu "I'uruor Burden per flssessutettt using irRC'criteria
accolults tbr the size nud s.lou,tlr kinetics of both old and ner.l,lesiotts as the,v appear.
Definitionof Index-!.s'-:trtu,:&upgUglJUttr ji$e
o ir(lomple{e l(eslronst (ir(iR): C ourplete disap;:earnuce of all iuitzx lesiotts This
bnseline in trvo obselatiorm
at least 4 wk apart
50Q'o clecrease in trunor
brudeu courparect rvitlt
ba.qeline cannot be
established nor 25o'o
iuclease contparecl rvith
naclir
A1 least ?5qir irtcrease in
tuurol burden compared
ivilh rraclir (al an1' single
tirrre point) in two
consecutive obsel-r'atiotts at
least 4 wk apart
categon errcorlrprrsses exactly the sante strbjects a.s "ClR" ti5,11,u
SD
PL)

Pt'otluct: Peuibrolizrunnb
58
Protocolr'Amendmrul ao., I, 
O
C 
fionfidan{ial
irPartinl Response (irPR): Decrease. relatil:e to lraseline. of 509,0 or greater iu the
stmr of tlte prodrtcts ol the nvu largesl perpenclicular diametels of all irrde.r and all
rle\v nleasurlble lesrous (ie.. Percentage Change iu Trunor Bru'clen). Note: the
appealan(:e ttf rten' ureasrual:le lesions is lactored into the overall lrunor -u-uder. but
cloes not autornatrcrlh qualiS,'as pr^ogn'essive clisease until the SPD iucreases by
:"?5o.,'o rvhen conrparecl to SPD at uadir.
irStable Disease (irSD): Does uot meet criteria for irCR or ir?R. in tlie atrsence of
pt'ogressive dr se'a sc..
irProgressive Diselse (irPD): At least f 59,b irrcrease Perceutage Charrge in Truror
Btutleu (i e.. tnkiut sunl trf the products of all lrrrlc"r lesious and any new lesir:ns)
rvheu corupared lo SPD at nadu.
Dgli$ltop_ _ot-Npp:irrcle_:i I,esiogl Respp16g...-Llg.irg..ir RC
r irComplete Response (irCiR): C"ourplete disappearance of all rrorr-nrder lesions. This
category erlcollpasses exactlv the same sulrjects as "CR" lry the m\\'HO criteria.
irPartirrl Response (irPR) or irStable Disease (irSD): tton-inde.t lesion(s) are not
ct-ursidererl iu llre det"urition of PR. these tenns do uot appll'.
irProgressive Direlre (irPD): lucreases iu uuurber or size o{ rtott-ittdex lesiou(s)
does not cr-rrtstittrle progressir-e disease rurless,'until the Percentage Clhauge il Tumor
Burdeu nlcre{ses br' 150,., (i.e.. the SPD at nadir of the index lesions increases by the
requir"ed amouut).
hupact of New Lesious on irR('
New lesions in ancl b1'theruselr,es clo uot qualifu as progressive clisease. However their
coutributi<-ru to totai tluuor Liurcleu is iuclucled in the SPD r.vhich in tunt feeds into the irRC
criteria for huuor respouse. Thereiore. uew non-measrrable lesiorx will nr:t discontinne any
subject frour the studr.
7.1.2.6.5 Dcfinition of Or"erall Response Lrsing irRC
Overall lesponse rrsins irll(" rvill be ba":ed on these criteria (see Table 9);
o Immune-Relrted ('omplete Response (irCR): C'oruplete disappearance of nli hnuor
lesions {index arrd uouurdex tosether rvith no nely rlea.sulnble/uruneasurable lesiorrs)
for at least 4 rveeks fl'our the clate r:f clocumentatir:n of complete response.
r fmmune-Rel:rled Partill Response (irPR): The suur of the 1:roducts of the two
largest petperrcllcullr diaureters r-rt'all iudes lexrous is ureasruecl artcl capturecl as the
SPD baselirre. ,\t each subsequerrt nlluor assesslne[t. the srurr of the products of the
trvo largest perpeuclicrrliu' cliameters of all jldex lesious ancl of rrerv ureasru'atrle
lesions ate added losefher to provide the Irruruure Response Suu of Plochrct
Diatueters (irSPI) j. .\ ilecrense. relative to ba.seline of the irSPD courparecl to the
{
pler,ious SPD lraselrrre. trl'-i0oo or sreatel is cernsiderecl au ir

Protluct: Peuibrclizrrnmb
Protocol/Arnentlrneul ao., I, 
O
C tonfidc*ti*i
(irPR)
r fmmune-Related Stable Disease (irSD): ilSD is dellned as the tailure to rneet
critelia fol itttttuute coutplete response or inuuune partial respc,use. i1 tlre abselce of
progressi,u'e rlisea;e.
o Immune-Relaterl Progressive Disease (irPD): It is recouuuenclecl in cliflcult cases
to conlir:tt PD bi' serial uuaging. .{n1,'of the follor.ving ivill constihrte proere.ssive
disease;
r At leasl l5o'o ittcteilse in tlte srurr of the products of all irrclex lesions over naclir SpD
calculated tirr the irrclex lesions,
I At least a 359o ulcrease in tlte srurr of the products of all index lesiorrs arrd uerv
0reasurable lesic,tts {rrSPD) over tlte baseliue SPD calc*lated for the irrdex lesions.
luuuure-Rela ted Besr_(.\gl ll Response Lrsiug irRC (irBOR)
irBOR is the best cottlinrtecl irRC' overall response over the shrcly as a rvhole, recorded
betweeu the date of tirst tlose uutil the last hruror assessrnent betore subsequent therapy'
(except for local palliative radiotherap-v t'r:r painful bone lesions) for the indiviclual subject in
tlre study. For tlrr' assessluenl of irBOR. all available assessruents per snbject are corrsiclered.
irCR or ir^PR cletemriualious incluclecl iu the irBOR assessmert rutut be confinned bv a seconcl
(confimtatorl') evaluatiori nrc'etius the criteria tbr response nncl perfomred no less tlran 4 weeks
after the criteria lbr rerponse are t-rrst uret.
Tnble 8: Derivation of irR(' overnll l.csponses
59
i sr.,i',t
1
{ Iner
,1:l^c,irt
,
I . \l,,re
1' { lttec
[.]1() gl
rureasura[rle
L)llse
Nomreasuable
re$ponse
Overall respollse
index lesiorr
Ner.v. uonmeasru'able
lesious
Llsing irRC'
:nl
r\bseut
ilCRi
e
Anv
ilPR"i
privocal
'r.ssit'lrt
.tn)'
rrPRt
:ttl stirirle
An-v
irPRi
rurvocal
essirxi
Anv
irPRt
:*]-
Meastralrle respouse
Iudex and nerr,.
rueasuralrle lesions
(fttutor t'rtutierr ) *,0,r

Product: Petttbroliztrtttirb
ProtocollAlnentllneul ao., I 
'o
t'_:----.
I Llrreiltrt
I pr,,*r**
i!_-_.._-_
I Arrr'
I
i
L
60
C 
Confidrntial
rtable
.tury
ru5D
rrocal
,siou
Anv
irSD
Ary
irPDt
*Decreases assessecl relntrve to birseliue. iucluding measurable lesions only l'"-5 ' 5 uun).
lAssuming response (u'('Rl r,utd plogression (ilPD) are cotfirrned by a second. cottsecltttve
assessurent at leasl -1 rvk il1lat1.
7.1.2.6.6 llethod of arsessntent
T|e same luethocl o1'asressnteut aud the sarne teclurique rvill be used wheuer:er possible to
characterize each iclentitlect irnd reported lesion at traseline and during follow-up. Iuraging-
based evnluation is 1:ret'ened to evahmtion by clinical examiuatiorr wheu both metliods have
been used to assess flte arttittuttot effect r:f a treatntent.
Chest x-rBy- Lesir-rrrs trrr chert \-r'tly are acceplatrle as uteasut'aL:le lesiorts wherr the.v are clearly
defined ancl surti-'ruuded tx aetatecl ltutg. Horvever. C'T is prel'erable.
Conventional Cf' antl \IRI- "l-hese tecluuques r,vill be perfomred lvith ctrts of 10 rruu or less
in slice thicluress contisuouslr'. Spiral CT rvill be perfornted using a 5 uun contigtlotls
recoustnrclir:n illsorithur. 'l-hir applies to ttuuors of the cltest. abdotuen. and pelvis.
tlltrasound ({.rS)- Becntse one of the eudpoints of the shrdy is otrjective respouse evalualiofl^
US will not be useel ttr nressute tluror lesious. US uright be used" af the discretion r:f the
investigator, to coulhnr the courplete disappear-auce of, superficial lesions assessed by cliuical
examirtatiou.
Cflology, hisfologr,- l'ltere teclutitlues uta-v be used to cliffererrliate tretlveelr partial responses
(PR) ald coruplete resl)ollses lC'R) if uecessat-v auil detemtined by the ittvestigator. C',r'tr:logical
conlinnation of the nei,rplastic r',rigin of any ettrsion tltat appeat's ol'worser$ during treatlrent
rvhen the ureasruablt. truuol' has nret criterin for respottse or stable disease is rtmudatory to
differerrtiate betrvr.en resl)olrse rrr slable tlisease (an etlirsiou tllay be a sitle elfect of the
treatmenti and progre.stve cliseirse.
7.l.2.6.1Definitiont Atrociatetl n,ith Response Evaluation Clriterin in Solid Tumors
(RECIST) r'ersion l.l
, !;i
1",:50 to -
l'':50 to
i.,l-i

Product: Penibrr.rlizttrinlr
PlotorollAlneudrnt'rrt to., I 
0
C Conlidrnlial
ilIensurable diserse
The preseuce olat lerrst rrne ureasurable lesion. If the umasruable disease is restricted to a
solitary le.sion. its nr.olrlasric uatlue slrould be corfrnued by c1'tology,'histology.
Me*suruble lesions
Ir{easurable lesions ilre cietirrecl as thLrse that can tre acctuately nteasurecl in at least one
dinrension (longest clianreter tcr Lre recordecl) as ::"!$ nurt by chest x-ray. as :""10 nuu rvith C'T
scatt. or' > 10 uun rvitlr caliper s tri, cliuical exam. All trunor lr]ea$uletnents mtmt lre recorded
in urillirnetels (or clecirual llactirlns ol cenfimeters).
lion-measurable Iesions
All other lesions (or iitr of disease). includiug sruall lesions (lougest diatueter.:10 uun or
pathologrcnl lvnqrh nork's rvith l0 lo .r l5 uuu short axis), ale cousidered nort-rnea.stuable
disease. Bone lesirirls. lL'ptolneningeal disease" asciles. pleural.tpericalclial efftrsiotts,
lyruphangitis cutis,puhironitis. irrtlauuuatory,breast disease. and abdorrunal tnasses {not
followed try C'T or lr{RI }. are cr:usideled as tron-rnessut'ntrle.
lr[ote: Ciystic lesious thrt rneel the criteria tbr radiographically detined siruple cysts should
ttot be considereci ils unlislaut lesious (neither measurable nor t]or]-oleasurable) since they
are, by detinitiur. sirirple c.vsts.
'Ciystic lesions' tltr.'irrsht lo reprelent c)'stic rlletastflses cau be consiclerecl as ureasurat:le
lesions. if thel'ureet thr. clelluitiou tif ureastuabiliry* de.scribed above. Hower.er, if non-c1'stic
lesious are preseut ur tirc, :irrne srrif ect. these are preierred for selectiort as lalget lesions.
Halignant lvmph nodes
To lre r..onsiderecl patholosicalir errlargecl arrcl meastu'able, a lyniph nocle tnust b" ,,'1-t nun in
short axis rvhen assessed Lrv Cl- scan (C'T scan slice thicllress reconuueuded to be no $tteflter
than 5 nurr). ,{t brselrne aucl iu li,llorv-up. oul-v- the sltofi axi.s rvill he uteasttred alcl followed.
Baseline documentrtion of 'oI'arget" antl "Non-Tilrget" lesions
T:rrget lesions.
All measru'al:le lesions up to a nrasinruur of ? lesions per organ aud 5 lesions in total.
representative ol all inr olr,ecl or garls. should tre icleutiflred as target lesions attd t'ecorded ald
rrreastued at baseline. l'arget lesious :hould be selectecl cu the basis of theu' size (lesions with
the longest diameter)" tre represerrtatir,e of all invoh,etl or$tfirrs. but in additiorr should be
those that leud theurselles to le1:r'oclucitrle repeated nleasurements. It rua-v be the case that. on
occasion. the lalgest lesrr-rrr dr:es uot lend itself to reproducil:le tt]easu'etrtettt in rvhich
cilcuustance the lre\t lar gc.sl lesiori rvhich can lre ureastu'ed re1:roducibly should be selected.
A suru of the diilnreter s llougest 1'or nrit-nodal lesir:ts. sltort axis tbr uodal lesions) for all
target lesions rvill be calcrriatecl iurd reportecl as tlre traseline strm cliarneters. If l-vrrrph nodes
are to be inclucted iu the surt . then oull' the shor"t axis ts added irtto the sutn. The bnseline
sruu diaureters u,rll be rrsed as reterence to ftlilher characterize any objec:tir.e trunor
repuession in tlte ureasruable rliruensiou olthe disease.
6t

Product: Penrbrr"rlizrrrnrrb
67
ProtocollAtnenthneut to.' I 
,o
7.1.2.6.r0
C 
Gonfid*niiel
7.1.?.6.8 fvaluttion ol'.t:rrget Lerionr: Trble g
7.1.2-6.9 Er"alurtion of \on-Tlrget Lesions: Table l0
Evaluation of Best Overall Response: Table 1I
I'he lrext t,r"utnll respol]se is the tresl lespouse recorded tlour the start o{'the
trestlltellt urttrl clisease trx'ogressionrrecrurerlce (taking as refereuce fcrr progu'essive
dtsease tlte sruallesf ueasruellrents recr:rrcled since the ireaturent starred). The
patierrt's l)r'5t respoltse assismnent will depend on the achieveurent of both
llleirsul'elniirrl arrd cril rfinnatiolr criteria.
C'ourpletc. Response {C'R)
Disappeararrce of ali targef lesious
Partral Respr.rnse (PR):
At least a 30q'o decrease in the srurr ef fhe lousest cliarneter
{LD) of target lesioris. taking as reference the baselite
suur LD.
Progressrve l)isease t PD):
At least a 20o,.o increase in the sruu of the LD of target
lr'sious. takius as refeletrce the srnallest suru LD recorded
siuce the treatment started or the appearauce of ole or
lnore fierv lesious.
Stable Diselse (SD):
Neither sutficient sluinliage to quali[' lbr PR uor
sutlcient increase to quality for PD. taking as ret'ereuce
the surallest uuu LD siuce the treatuent stailecl.
C'ou4rlelc. Reslrcuse ( ('R )
Disappearalce of all non-target lesious aud
tuonnalization of ftunor uiarker level.
Incouryletc. Response
Statrle Diseasc. iSf) ):
Persistence of one or ulore non-tarqet lesiot(s) and,'or
utaiulenarrce of nurrol marker level a[ror.'e lhe nonnal
lirnits.
Progressive Drsease ( PDi
Appearance of r:ue or lllclre new lesir:rrs aucl,'or
runequivoca I progressir:l of existit g llou-talget lesious.
Although rt cleitr prooressior of "ilon-targef" lesir:us oulv is exceptional, in suclr
circrunsturrces the opiurorr of the investigatol'lvill prevail.
*Note. Il- ttuttor utarkels are iuitially above the upper nolmal liutit. they rrrust
nonnalize tirr rl patieut lo lre corxidered in cour;llete clinical re$poilse.

Pt'orluct: Perubrolizrurrah
Protocol/Arnentlmenl ao., I 
,,0
63
C 
Crrnftd{inrirt
Tatqet L.e:iorr.
\orr-'I'alsel Lexions
Ner.r Lesiorir
Or'erall Response
No
No
No
('R
('R
PR
SD
PD
PD
PD
PR
SD
PD
.{l}\
CR
lrrcourplete
lespouseiSD
Non-PD
Non-PD
Aly
PD
Aly
jrio
Yes or No
Yes or No
Yes
CR
PR
-&r-r
Notes:
Patielts rvttlt a global cleterioration of health stan$ requirillg chscontinrmtion of
treatntettt u'tlltouf oblectir"e evideuce of disease progression at thnt tirne should be
classilietl rrs havilu "syulptomatic deterroration..' Every elfort will be made tr
docuurent the objectii,e pro gressiou.
In soute ctrctuustances. it rnay be tlifficult to distingtrish residrral disease fi.our
ttounal tisstte. \\"'ltett tlte evaltmtion of complete lesponse clepends ou this
clelentrirrttt,ut. the tesitlual lesiou will be irvestisated (fine needle aspirare,tiopsy
if possibll lrelbre conli',iug the coruprete response stanlsi.
7.1'2.7 Tumor Tissue Clollection and Correlntiye Studies Blood Sampling
Mauclatory stttrriliiisiott o1'unstiliucd xlicles frorn an arclrive{ tlupor trlock for PD-Ll arraly'sis.
Sifes rlrtlst veritl'that arr nrchived ftuuor block is available ro obtaiu mrstaiued slides fr.our
prior to registratiort to tlte tr"iai. L.lrtstairrecl slides suburittecl tcrr PD-Ll stniui,g u*rst be cut
aDd sent withiu 7 clnvs oi attall'srs. A fresh biopsy is NOT nranclator'.,,, to parriiipate in this
trial.

Ploduct: Pentbrolizrrnr;tb
Protocol/Amendrneut ro., I,, 
o
$ 
Cordilrntirt
A line reedle a$pirate. fiozen saluple. plastic emt'redded saulple, cell trlock. clot. boue. bo,e
uunow or cltok:rgic specimen are uot be acceptatrle tbr pD-L1 analysis.
Please refer to the Snrcli Proceiiur es l\{auual for processing. labeling anct shipping iustructions.
7.fJ Laborntorv Procedures/Assessments
Details IeSardur€i specilic laboratr:r-r.'procedrues/a$sessruents to be pertbmred i1this trial are
provided below. Labor:ntory Safeg'Evaluations (Henratology. Ctreuiistry and Urinalysis)
Latroratory tests lbr heuratologl'. cheruistry. atd others are specitied i1Table 5.
64
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Pt otlucf: Peuibroilzrutmtr
Protocol/Amendrneul So.: f 
, O
1S Ctttet"tirt
Laboratory tests ftlt (creeni$S or erltr) into tlre Secoud Comse Phase shoulcl be pert'omred
within l0 days 1>rior to the first dose of tleatolent. After Cycle l. pre-d,cse laboratory"
procedures cart be ctrnclrtcted up to 71 houls prior to dosing. Results mr*t be rcviewecl bl,'the
investigator or qualil-red desigrrc'e irrrcl lbrurd to be acceptable prior lo each dr:rse of trial
lreatruent.
7.1,3.1 Pharmacokinetic/Pharmacodynamic Evaluations
As PK data have prr'\'iously been r'xauriued in other cliuical tr:ials. we clo not anlicipate tlre
rteed to pertbnrr PK testing rurless othenvise directed b-v the Spousor.
7.1.3.1.1 Blood (lollection for Serum Pembrolizumab
Santple c.ollectiou. sttrraqe autl xhipnrent iustr"uctions for sennn saurples will be provided in the
Laboratory lt1armal.
Tlre tirnepoints t'or PK blood sanrplilg are described iu Section 6 - Trial Flor.v C'hnrl.
7.1.3.1.2 Blood (lollection for Anti-Pembrolizumab Antibotlies
Saurple collection. storage ancl shiprneut irrstnrctions tbr bk-nct samples will be pror.ided irr the
Laboratorl Maluml.
7.1.4 Other Procetlures
7 .1.4.1 lVithdrar,r'ali Disconrinurrtion
When a subject clisc,.rutinuesirr,rtliclrarvs prior lo tr:ial cotrrpletion. all applicable activities
scheduled tbr the t'irirl trial r.isit .should tre pertbnued at tlre tiure of discontinuatiou. Any
adverse e\reuts r'vhich are present ill tlrr. tirue ot'discontinuatiorr&villrdrarval should be followed
in accot^dzutce 'uvitlt thc' sa{bty requireurents outlined iu Section 7.? - Assessing and Recording
Adverse Erreuts. Srrlr.iects rvho a) al(nirr a C'R or b) coruplete 36 doses of treatuent with
pembrolimntab tnal' dtscontiuue treatureut with the optiou of restartirrg treaturent if they ureet
the criteria specified irr Sectiou ?^1.5.5. After discontirnring treatment fullowing assessruent
of CR, these sutrjects slrould reluur to the site for a Satety Follow-up Visit (described in Seclion
7. 1.5.3.1) and then pr oceed to the Ftrllorv-Up Period of the studl' (clescribed in Sectit'rn 7. l.-5.4).
7.1.4.2 Blinding/t'nblinding
This is,ul open label trial' there ir rro l:liuding for this frial.
7.1.5 Visif Requirements
Visit lequireruents i'rrr' outlilled rn Sectir:n 6.0 - Trial Florv Chart. Specifir: procedrre-r'elated
details are pror.idecl ;rb,,ve iu Sectiol 7.1 - Trial Procedures.
66
tlii
ta ! l

Produet: Peurbrolizrunnlr
Protocol/Arnenttrnerrr to., I 
o
G Confidirtisf
7.I.5.I Screening
Approxiuratel.v 28 slavs befort' beatmting treaturent. potegtial sutrjects will be evaluated to
detenlrirte if they frrllill rhe eligibilitv cr-iteria. Tesrs perlomred before the subjec.t signrs cousent
nre penuitted as lotg as tlrey ar^e pertbnnecl r,vithin the appropriate time frarire lru p"r t[e traii
flow chart' Sutrjects ruay be rescreened afler thilirrg to ureet tfue incluiorrexclusiol criteria.
Please seen the trtal ilorv chart is in Sectiorr 6.1.
7.1.5.I.1 Screening Period
The scree[irg perioci rttay last ti onr I -28 days as long as the s1lrject is atrle t6 have l]ece$saly
testing corupleted iu tlie apprnpriate time frarues,
7.1.5.2 Tre{trnenl Period
Section 6. I details tlte treatment peuod. cousistirrg of 6 weeks of chemoradiatiol tSerapy a,cl
then initiation of the peurbroliruuatr er:er1, 3 rveeks for up to l8 cycles. pernbrolizurnab will
be incorporated dru'ing cheuraradiation bv the phase i trial.
7.1.5.3 Post-Trealrnent Vi*its
7.1.5.3.I Safery Follorv-I"lp \/isit
The mandatr:ry Safetv Follorv-I-lp \:isit should be conducted approximately 30 days after the
last dose of trial frealtttent or trelirre the iuitiation of a uew auti-cancer treatulent. whicherrer
comes first. All AF.s fhal occur prior to tlie Sal'ety Fr:llorv-Up Visit should be recr:rded.
Subjects rvith an AE trt'Grade ;," I will be fullowed rmtil the resr:lution of the AE to Grade 0-l
or urtil the begirurilg ula uew anti-neoplastic therapy. whichever occu's first. SAEs that occru.
rvithin 90 clays of the crrtl of trealnreut or before iuitiation of a nerv anti-cancer treatment sliould
also be tbllorved ancl t ecorded. Srrbiecls who are eligitrle for retreatmeut rvith perubroliaunatr
(as descrilred in Section 7.1.5.5t urav lmve up to two safety follorv-up visits. oue at]er the
Treahneul Period ald one atler tlie Secoud Cloruse Phase_
7.1.5..1 Follow-up Visits
Subjects rvho discontirure trial tleahueut for a reason ertlrer than clisease proEu'ession will urove
into the Follow-Up Phnse and should be assessed every 12 rveeks (* 2 weeks) by racliologic
iuugilg to utouitor clisease stahrs. Atier I 1,ear, the iuraging tiure point will occur every l6
rveeks (* 3 rveeks). I.r c'ry effort sliould be made to collect infcuuation regarding disease status
rurtil the start of uerv lnli-neoplastrc therapy. tlisea.se proer-essiou, cleath. eucl of tfie shrdr, or if
the subject begiru retreatuent rvith pernbroliztuuab as detailed il Segion 7.1.5.5. Inforuration
rcgarding post-shtdv attfi-ueoplastic treaturent u.ill be collected if nerv trentntent is irritiated.
Srrbjects who are elisihle to receir,e retreatulent lvith pembrolizrruralr accor<ting to the criteria
in Sectiou 7. 1.5.-5 rvill ruove ti'onr tlte lirllsiv-up phase tr"r lhe Secoud Cotrse Pliase rvheu they
{

Producf: Penrbrohzrrrrrnb
ProtocoliAlneudrnerrr so., I 
o
C Gonfidr*ti*N
experieuce dircase pr'0glt$siou. Details ere provided in Section 7.1.5.5 - urd the Stu{y Flow
Chart (Table 6) tbr Retreatruent.
7.1.5.4.1 Survivsl Follow-up
Once a sulrject expetieuces confirnred disease progressiou or starts a new anti-cancer therapy.
the sudect trlolres into the sul,ival tbllorv-up plmse and shoulel be contacted by relephone
every l2 rveeks to assess for sturival stahrs rurtil death. withdrar,val of consent. oi the end of
tlre shrdy, rvhichever oc:crus t'u'st.
7.1.5.5 Second Clourse Phase (Retrearment period)
Subjects who stop pembrolizumab rvith sD or lrettel uray tre eligible for up to oue year of
additioual pernbrolizrrmab tlterapr, if they progl'ess after stoppirrg shrdy treatl)renr. This
reheatrttent is terxretl llte Secorid C ourse Phase of tlris shrdy and is r:nly available if the stud1,
remains open and ttre subject rleels the t'ollowing conditiorn:
o Either
Sl,:pped rrrrtial trealtnettt rvith pernbrolizurnitb alier aftairiuq au ilrvebllsilt()l-
detenniur.tl cout'irrued ('R accorcliug to RECIST 1.1^ nnd
' 
\\irt" tteatecl tbt rtl k'itst l-l lveeks rvith perubrolizrunab betbre cliscontiuuiuq
tltet lipr'
' 
Reccived at leart t\\r) lleallllents rvith peurbrolizuurab be-voucl the clate rvhen
the rrrrtial C'R it'lr declarecl
OR
Had SD. I'l{ or C'R nrrtl stopperlpenrlrrr-rliaunab treaturerit alter l6 closes of shrcll'
tltelapv ii,r reasons othc.r thal chsea.se progressiou or intolerabrlitl
A\'D
r Experiencecl iut iuvestigakrr-deteruiiueci couiinnecJ lacliographrc clisease procressir)rl
attel stoppiue rheir iuitial treaturent rvith pertrbroliztnnab
r Did ttot receir e lttl' attfi-r',urcr'r trcirtl))ent since the last close of petrlrrr:lizunratr
r 
Hns a pet'lbtttt:tnce statlrs rrl'0 or I on the ECOG Perforrrrauce Scale
r 
Detnott^straler rtclequate r.rrsiru liurctiou as detailetl in Section 5.i.2
68

Protluct: Peurbrnlizrrrunlr
Protocol/Alner(trnerr .o., I 
o
1$ eonnantiar
r Feutale *ubiect of clrllclbealiug poteutial shoulel har.e a negative selrrl or tu.i,e
prcgrancy test rvitldn 72 horu's prior to receiviug retreaturelt with stldy r*edication.
e Feruale subjer:t of ehilcltrearing potential should be willing to use 2 uretlrtxls of birth
coutlol or be sugically riterile. or abstair fi'orn heterosexual activiry- tbr the cotuse of
the study tluutrgh I20 da-vs atter the la.st dose of sftrcly ureclicatiou iR.f"."rr." Sectiou
5'7'?)' Subiects of chiltl Lrearirtg potential are those rvho have rot beeu sru.gicall;-
sterilized o'ha'e been fi-ee fi.or,,re,ses for :-, I year.
r Male subject slrould a€rlee fo tlse an aelequate u]ethod of coutraception starling rvith the
first dose of snrcly therapl' tlur:ugh 120 riays after the lasr dose oi stucly tlerapy.
o Does not hare a [ristory or L'urteul _eviclence of any condition. therapv, or laboratqry
abuonualitl' that nright irttet fere with the sutrject's participatiorr for tlie f*ll chualiorr of
the trial ol is ttot in the best interest r:rf the sirbjectio participate. in the opiliol of the
treatirrg inve,l i galor.
subjects rvho restat1 lrenhneut rvilt tie retleatecl at the sarne close aucl dose iulerval as when
they last received Pc'tttlrlolizrunalr. Treaturent rvill be ackuinislerecl for up to orre additio,al
year.
visit requirements are outlined irr section 6.0 * Trial Florv chart.
7.2 Assessing nnti Recortling .drlverse [r.ents
An adverse event is definecl {ls .rny rurtoward rrredical occull'ence iu a patient or clilical
investigation sulrject.adtiinistererl a phannaceutical product apd wlich cloes not necessadly
have to have a carsal relatioriship r.viilr this treatmeni Ar atlverse event can theretbre te a11y
rufavorable aud tmitttended sigrr {includins au abuornral latroratory tincling, tbr exarnple).
syruptofir. or disease temporall-v associatecl with the use of a mediciual pro&rct or protocol-
specified procedue. n'hetlter or not cousiderecl relatecl to the ruedicinal pr,:.luct or protocol-
specitied procedure ,fuiy -wr:rsening (i.e.. an-v clinically signiticant ach,,erse ciralge i1
ti'eqttertcy ancLrol interrsitl') of a preexisiurg conclition rhat is ierrrfc,rall1, associatet{ ivitl t1e *se
of tlre Merck's prorhtul. is also an ilrhrerse everlt.
Chailges tesultiug hettn notlual srorvlh ancl der.elopment that do not v-aq/ significastly in
frequency or s.vei'il.' ti'orn expectld levels ale not to te considered advers* .u.rrir. Exaurples
of this rnay iilcltrde. bttl are nol [mited to. teething, rypical crying in infhlts alcl chilclre,2r4
onsel of mellses oI' ntE.rlopalrse ocuu: ing at a physiologically appiopriate rigre.
69
IprcttocoI-s1l.,ertiedpl.ocl,(hu.e.rvlref1l
cotul)alator trteclicntrrrrl)oI martetecl. trauutircnrrecl br.. liceusecl b1'. provicie,l t',1, o,
I
or actlve
distlibuted

Protluct: Penibrolizruuab
Protorol/Alneudrneut So,: f 
,O
C Confidr*tial
Adverse e\'.etlts 1l]8\' or.'cul' dtuins the course of the use c,ffproduct il clinical trials or
rvithin the fcrllorv-up period specilied b-v rhe protocol. ot pr 
,l i1 clilical practice, ti.o*r
overdose (rvhether ace rcleutal or irrlentional). frorn abuse and tronr withdrar.val.
Adverse evellts uray" also occur iu screened subjects chu'ing any pre-allocati6u baselile periocl
as a resrtlt of a protocol-specifietl intetventiotr. inclut'lirrg rvaslrllrt or cliscoritilrmtioil of usrml
therapy. t{iet. placebo lre&tflreill or a procedrue.
Progression of the crr)uc'r'urrrler slrrdl' is uol considererl an adverse event ruiless it is considered
to be drug relateel trv ltre ilrvestisrrfeir.
All adverse evertts rvill be recorclecl ti'oru the time the consent tbnu rs sierred iluough 30 clays
follor.virlg cessatioti r'rt'tteahuent iiud at each examination ot the Adverlse Evert iase report
fonnsil'votksheets. Tlre leporliug tinreti'aure for atlverse events ureetilg agy sedops criteria is
described irr section 1.1.3.l.
7 -2.1 Definition of rrn Overdose for This Protocol antl Reporting of Overdose to the
Sponsor and to $'Ierck
For ptrrpr:ses of this llral. au overciose of perrrbrolizurnab rvill be cletined as any close of 1.000
It}g or greater (:'5 ttrues tlte iridrcated dose). No specific infcrmration is available on the
treatment of overclose of pernbroliztuuatr. Appropriate srryportive treatuent should be provicled
if clinically inclicated. In the evenl ,,rf overdose, the sut:iect shoulcl be observecl closely for signs
of toxicitv. Appropt i;rtr' supporlr\ r' treatt)]ent shor.rltl [e pror,iclecl if clinically indicatetl.
If an atlverse event(si rs Rssociirlecl rvith ("results fi'om") lhe overclose of a \.{erck procluct, the
adverse e!'ent(s) is tep,rrted as a serir:us arh,erse event. eveu if uo other seriorrrrr*ri criteria are
ruet.
l::.:ffi:tilil*H::ili',',xiT,i:ilr,:::,i:,1lilii-:;,:ffi',i:::',:i$:ixi'l'::::,:?:
sedons Etent of (.iiriical Inlerest (ECI). usurg the teuuirrc,logv "acciclental or intentional
overdose rvithout adr erse effect."
All reports ol ot et'clo.,u ivit[ aurl lvit|out al a{verse er:e1t ulrst be rep6fle{ rvit[in ]4 h6urs t<>
the Spousr"rr arrd rvithru 2 rvorkurg clay,s horu's to lr..{erck Globnl Safef_v. (Attn: Worldwide
Product Salbtl,: FAX :15 993-l:10)
7.2.2 Reporting of Pregnanc' and Lac{ation to the sponsor rnd to }Ierck
Althotrgh pre€$lanc-v iurcl lactation nre llot cr,xrsiclered aclvelse evellt.r. it i.s the responsibililv 6f
invesligators or theil ilesigrrees to r eport alr\r pregllaucy or lactation in a srrtrject (spontaneou.sl-v
reporled to tltem). ile lrrcling the pt etnancv of a ruale subject's lbruale partner that occurs cluring
tlre trial or rvithin 110 Llays of ct,nrplerirrg the trial coruplefing the ti-ial, or 30 cbyltollq*-rnp
70
9' 11
l', ir
c'essalion of lrealnteur if the sub.iccl iuitiates nerv antitrarrcel lherilpy. rvlichever

Pt'otluct: Peurbrnlizrunab
Protocol/Arneudmell to., f 
o
G Confidrntiel
subjects.and tbrnale pal'tuers of urale snb.iects who becoure pl'egilant rurut lre ttrllowed ro the
completioultemilnation ot- the |rlegnanc),. preguancy outcomes of spontaner:us abortion.
srissed al:ofiiott. berriql hydatitlilburt ruole. blighted'ourur. tbtal cleatir. iutrauterine deatl.
tuiscarriage ald stillirilth ruttst tru repollerl as ser"ious events (Inrportar)l l..Iedical Evegls). If
tlte preguraucy contfulttes tD teruI. the outcome (trealtlr of itfant) nrust also be repqrlecl.
such eveuts uurst be lepoded u.rrlriu 3'l hours to rhe spr"rnsor ancl
2 rvorlcing elays tt:
7.2.3.1 Serious Adverse Events
A seriotts ndverse el'ertt is anv ach'erse el,ent occlm'ing at auy close or duriug auy rxe of
Irlerck's producl tlrirr
o Results in dearh.
o Is lif'e flueaterrrng:
o Results in persistent or. siqrrificant disabilitl,/incapacity:
r Results ir or liroh:rrgs ari existing iupatieut hospitalization:
o Is a colrgeuitlrl ilnonmlv Lrrrth cletect:
r Is a uew carcer (thnt is nol ;r conditiou of the shrtly):
o Is associatecl rvrth an or,er rlose:
o Is an olher inrputaut uredical event
Ref'er tr: Table 6 fcrl ridclitional details regarding each of the above criteria.
Ptopu'essioil of the callcer urrder rtrdy i5 not colxidered au aclvelse evelt urless it results i,
lrospitalizatiorr r:x dea Ih.
Any serious adverse cleut, or tbll.rrv llp to a serious adverse eveut. incluctirrg death chle to aly
cause other than progression of the caucer rurder studv that occtu$ to any subject fiar, the tirne
tlte consent is signetl tlu'ough 90 clays follorvirg cessation of treaturent. or the initiarion of ,ew
anti-caucer therapv, rr,hiclrever rs erulic'r. lvlretlier or not ltlated to
7l
leported rvithin 2-l h,,rrirs to the Sponsor-hrr.estrgator' (repor
Ivledwatch -1500A tirrrn 311^.,,r,i1. please see DCp for arltliti
Sponsor-Investigator rvill reporr t'r'eut to
aware of event.
Nou-serjotr Events r,l'C'linical hrlerest rvill be tbrwarclecl tt-r
harrcllecl in the sarue nu.uurer as S..\Es^
ithin 24 horrs of becomins
Additionally, arr). serious
physiciarr to lre relared to
ildr,er se e\iellt. considered trv att investigatol rvho is a qnaliflecl
frat 
is lrroughito the atrentiou of the iuvestisator ar
', i,

ally tilne olltside of the tinte perrod specrtied in tlie pler,ious pnlflgraph nlso ruust be reportecl
inurrediatelv to the Sponsor autl t, f
Plotlnct: Pembrohzruuntr
Protocol/Arnendrnerrt to.r I 
o
, 
.-1 .,..,.,., 
,, rI 
rrL,,rlrr 
rrr.,LL,,r,!r 
r _ ! -
l-ltrs Proloctrl rrrrrl Relrorturg rrl'( )r'er<lose lo tlre Sporrror. thi'rt
svtnptotus ol abuonrrll latroralrrlr lt'srrhs.
2. ful elevatecl ASI ,,t'ALT lirh rrltte tltat is grertef than ot ecpral to 3X the upper limit of
nonual anrl at eler;rtrcl total Lrilrrubiu lab r,alue tlmt is greater than or equal to 2X the uppet
liruit of uomtal and. at lhe saure liure. all alkaliue phosphatase la[r value that is less than ]X the
upper limit cf uolrrirl. as deteliuineel b-v way of protocol-speqified lalroratoqv testu]g or'
rursclteduled laborat,.rrv teslirrs.'i
*Note: These cr ileria are Lrased ttp6l availatrle regulatory. eliclalce docurueuts. The
purlose of rhe clrteria is to rlrc'city a ttuesholcl of atxronnal hepatic tests that may require
an additioual evalttatiou for ln underlying efiolog-v. The trial site guidance for assessurent
aud tblk:rv up ol'lhese crilena call be tirrurcl iu the hrvesligalor Irial File Binder (or
equivalent),
3. Adclitioual adverse events:
72
C 
Confid$ntirl
SAE rePortr and anv other rclcrrrnt sateh, inform:rtion rre to be forrvtrdeel to tfr.!
Global Srfeq,facsiniile number: I
A copl"of all l5 Dar Reports anilAruural Proqless Reports is submittecl as requiled lry FDA.
Eiu'opean Llttiott (Elt1. plrnt rracctttical and lvledical Devices ageuc.v (PN{DA) or ot}rer local
r-eqtilators. Investigator"s rvill cr,r's lel'ereuce lhis *ubrnissiou ace-ordiug to local regulaliorrs to
the lr.'Ierck IrtvestigalitrnRlC.otrr1r.,rrnclNurrrLrer(IND"C.SA.etc.)@
Additionalll, inveslrirrtors rvill \rrl)1rlit a copy of lhese lepolts to
at the tinle of sub@r-
iestrgator rs respollsl
br ct.nuururication to the FDA.
All subjects rvitlt serruus adverre cvents uutst be tbllorvecl up fol outcorue.
7.2.3.2 Events of C'linical Interest
Selected nou-seriotts rnd serit,rr. rr..h'tlse eveutr ale also klou'n as Evenls of C'lilical Lrterest
(ECI) arld ttttst be reeortled i:ls \uch on the Atlverse Event case leport fbmrsi'rvr:rksheets aud
reported rvitbin 24 hours to thc Sporrsor-Lrvestigator (report to RC'INJ via OnClore rvith
lv'{eclWarch 3500A lirmr attached. please see DCP tbr adtlitiorral reporting direction). The
awflr"e of evenf(A
tbr this trial inch
houls of Lrecr:uriug
s of cliuical iuterest
Delurition of an Overdose for
is uot associated rvith clilical
Sponsor-Itvestigatt"rr rvill
e r ettt tcl

Pt'otluct: Pernbroliziurrntr
Pl'otocol/Amexdrneut -o., I, 
o
C *onfidrr***l
A sepamte guiclance docuurenf has lieen provided entitled "Even{ of Clinical Interest
Guidance Doctuuent" (previi,rrsly eutitled. "Eveut of C'linical Interest and Inuuure-Relatecl
Atlverse Event Guidance I)rrcurr]€rlt"). This docurnent provides gnridance regardirrg
identification. evitlnafion nurl uranagemeut of ECIs aud irAEs.
ECis (br:th ttolt-serious autl rer ious adveme erents) iclentifiecl in this guiclance docrurent
t'ont the date of tirst close tlri,rush g0 clays tollorviug cessatiou of treatureut. r:r 30 days
atter the initiatii,rr of a ttc't rrnticancer tlieray:r'. rvhicher,'er i*.orlr"r.rr*"d t
tvitltrrt l1ltotus t,, lh@rg 
rlavs to
reporting guidelines.
Subjects shotrlcl t>e assesseri 1i'ir possible ECIs prior to each close. Latr results should be
evaltmted artd srrir.iects sltorrl.l tre asked for signs aud svnq:fo[rs suegestive tlf an inuurure-
relateel eveut. Srrltjects wir.., lle..,elop an ECI thought to be iuuuture-relatecl shonlcl have
additional testil)!: to utle orrl ,rther etiologic causes. If latr results or svrnptonrs inclicate a
possible irruttuuc-r elateel L( I then aclditionaI testiug should be pertbnned to nrle out other
etiologic catrser. If no othcr c'iluse is foruicl. then it is assuured to be inuurure-related.
7.2.4 Evaluating Adverse E'r'ents
An iuvestigator wlto is a qualilic,l phvsician rvill evaluate all adr.erse eveuts according to the
NCI Corrunott Tenuirtology tirr .\dverse Eveuts (C:'I'CAE). l.ersion 4.0. Any adverse event
which changes CT( AE grade t,r er the coru:se of a given episode r.vill have each change of
gade recorded on the adverse e\.r.ut case repoil fonnslworksheets.
All adverse events resafdless o1'( 'fCAE grade rutmt also tre evahraled tbr seriousness.
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Confid&nri$t
7.2.5 sponsor Responsibilitr for Reporting Ad'erse Er.ents
A.ll Ach'erse Er.euts r,,,ill be'cl,,,lte.l l* regulatt'uv a.thorities. IRBiIECIs a,d investisators i,
accs16[i111sg' rvith all lrpl:licahl.' ul,;bal lau,s ancr requratious.
8.0 STATISTICAI" AI{ALI-SIS PLAS
8.1 Stlfistical An:rlysis Plal Sunrmtrv
A sclletua fo evalrtrl," llie sillitr i,t'rilutiristeriuu pc-nrbrohzruutb rvith cheurolacliatiou (('Rl')
is provilleclbelou'. Sttccessive t cgituens have plo$essivelv lorigel colcur.erlt tre.nnent tlmes
going tr'oru post ractrlrtion. to I rveeks or.erlap. to (r rveek overlap if toleratetl or iucrease lr.{K-
3475 tlonr I \'rGQ 1 \\''EEKS li., I urs Q 3 \\IEEKS. The sa6n, is evahmrecl rlu.ouqh close
linriting toxici\- (DLT) c6115i'ling ol starle .1 pnernnoniris. fhe j+,-3 clesigu rvith close de-
escalatiotl anel starltrts. at Resiritett I u,'ill be useci to tilcl tlte nrasiunun rolerlalecl rlose flr{TD)
teqitttett. After \lf'l) rs l'otutrl 'is rttore;rntients n,iil be tl"eate(l at N{TD close regi,reu tbr a
Lretier elaltration ot'the satetr' ',1 llrr' rkrsing schechrle tirr liulher snrclr.. Tle cletaili .f rhe j.3
desigt rvith dose de-cscalatrorr iu e shorvn beltxv
Da-v 0 is the slart clal tor cheurlrittliiltrnl (('RT)
Dny -l) is the presurtecl last dnv t.r1'cheruorilcliatiou
Talile.X: Tnal Deslgrr
t
lDay0
turg
rruab
Peurbroliztunatr
Dose
Regiurerr
100 urg
Q3 \VEEKS
-t
200 rng
Q3\\TEEKS
I
.l00 nrs
Q3\\,rEEKS
l
100 mg
Q]WEEKS
,)
100 utg
QiWEEKS
J
200 ure
Q3W[EKS
-. l- r -.r ..
lDay0
l
l
START of
Pernbrolizuruab
2-6 WEEKS
AFTER C'RT
].6 \\TEEKS
AFTER CRT
] WEEKS
BETORE END
OF CRT
: $'TEEKS
BEFORE END
OF CRT
At start of CRT
Day of srar
Peurbrolrzu
llr
Day 56-s I
Dav -56-S l
1

Protluct:
r
C 
Conlidrnri;rl
With startiilg dose t'egimerr I . rr ()ul)s of 3 patieuts rvill be eutered at a tir:se level:
e If all 3 pafiertts treatetl irt tlte'dose resirnr'n do not have a dose linriting loxicit.v
(DLT), then the dr:se rvill be escalated to rhe uext close regiureu.
I If 1/3 patients have DLI', then 3 urore patients rvill be treatecl at this cl6se level. If
none of tltese additiolal patrents has DLT. then the dose will be escalated. otherw.ise
tluee more patiettls at'e tlcated at the prior dose regimen (if at rnost 3 patients were
previously trerted at thlr pr.iur.close rigirrren).
I If at least li3 ;:atients hnve DLT. then tlu'ee rrrore patients are treatecl at the prir:r 4qse
t'egimeu (if at rrrost 3 patreuts rvet'e previously trealed at that prior do.se regirueu).
The MTD is the dose regittiett that 0:6 (or0i-1 if at dose level *l) or Ii6 patier:t expedente
DLT: aucl at leasl 2i'i or 216 patrerrls treaterl rvith the next hishel close regiment ivill har:e hacl
DLT.
Note: If tlte escalatioll r)ccuts at the last dose regimen (Regirnep 5). t1e, the N{TD is at or
above the ]ast dose re.gitttert. I1' t ltc' tJe-escalatio,, o..,r', at tlo-se reqiuren - I (ar lea.st 2 o.l of 3
patients orat least 2 rrttl of 6 pltteuts have DLT at close reginreu -l). theu lhe l\,{TD is tlelorv
the dose regitnen -1. Iil either'(i1se. the NITD is uot cleteininecl trr:nr the trial. But tbr the
fotuier. the last reginreu {Regi,rr'u 5) is sale antl still can be usecl sal'ely fcrr huther shrtlies.
8.2 Statistictl Annlysis Plan
The strndy rle*igrr is showu irr Srrrclt,Design,Clinical plan Section. Table I gil,es tlree difl.erent
scenarios tor the probelrilities o t' toxrcig i.rt the close regimeus, In the tirst scenario. we assrune
dose-toxicity rates sttclt that tire |ate is -5oro at close level *l anti inc.reases graclually tr: j09,ir at
dose regimeu 5. hr the second sueuario. we irssurlle dose+oxicity rates such that the-r'ate is l29t
at dose regitneu -l arrci509o at tlose tegiuten 5^ In lhe thilcl sceuario, the close-loxicil' rate is
30,'ir at dose regiuren - l and inclrases sltiwly to 50o,o at tlose regimeu 5.
:riar tos of
bil
ft
le
I)ose
Reqinren
Irit st Sce rrr
Plobnbilr
Trrsir t
les oI loxtcltY al dr)Se levels
rio o1
-v of
Secontl Sceuario ol'
Probabilit-v of
Toxicity
Third Scenario of
Probabiliiv* rrf
Toxicitv
012
0. l5
0 ?I
0.38
0.38
0.50
0.03
0.0.1
0.06
0. l:
0:6
0.50
- ---eg:
0.0s
0li
i.).1.1
(). .l r;
0.5{}
Table 14. Tluee sr.
Startiug close levc.l
'.n
i i.. ..

/d
G 
Conlidtnil:l
For the secol}dsly obiective. Kaplan S'leier estimation illethc]d is used to e*timnte the rates .f
local and distant tuetastasis-free sturival. progression-fi'ee sruvival. a11d overall survival. The
contpat'isotts to tlte hrstorical (i)lttl ol\ ru e perftrnnecl using one-saurple log-ragli test. Local a,cl
distant nretastasis-li'et" xtrvival ts <lt-'tlrrecl as the eveut rvlthoul rer-lrrence wilhir the radiatio*
field (i.e. local - plaruring tru gel voltrure) aut-l outsit{e of the racliation tield {i.e. clistance - in
other parts of the htlu) r)r Iecttrreltce iu r:ther orgaus. Progu'essiou-ti.ee sturrival is the er.ert
rvithout sippr of flrlY proqressiou either locatl-v or: clistantll:. ureasrued tiour the initiatio* of
chemoradiatiotr' Overi'rll stuvival is the or.erall longevitl, oi tlr" patient finru time of iuitiation
of cheruoradiation lo liure o1'rleiitlr.
Frorn Table 1. the prr"rbabilitl thnt a dose regiruen rvill be cleclareti as t1e I9ITD is calcllate4 i,
Table ?. Also included in Tatrle 2 is the target toxicity level (r.e.. the pr6batrili6' r:f toxicit_v at
the MTD. if IvITD is clete*ui,ecli, the gi'en dose'egirrre*.)
Table 2 shor.vs tbat ntost likelv the resimen 2 will Lre declarecl a.s \.{TD rurcler the tirst toxiciry
ruodel sceuariQ. For Scertarios l. Regiruens I aut'll are likelv tg be the N.{TD. For Scermri*
3. Regimen 3 is likelv to be the \lTD. There is less thau a ldo.6 chance thar the lr,ITD caruror
lie detemdilecl tlorrr tlrt' trial in rll tl:re scenarios (3.3o0. -1.,1% au4 8.Jo.o lirr the lst. 2ncl a,cl3rd
scenarios, lesp*cliveh' l.
llif
l\ 
i 
r
Imffi"Hu,\o.:Io

Dosc'level (i)
P(DLT at di)
8.3 Scenario I
Sceuario ?
Scenario 3
P(cleclare l\lTD
Regiruerr i)
8.{ Scen:rrio I
Sceuario l
Scerurio 3
P(]I{TD": Regiureu
P(MID.{ Regiuren
P(MTD{ Regimen
C Contidsnriat
Table 1-r: 'l-iu'ee scerarios of p(DLT) at eacir tlose level iurclprobabilitr.of
i9
005
t). l:
0.r,,1
0.08
0.1-5
0.04
0. l5
0.21
0.06
0.24
0.?8
0.1?
0.36 0.50
0.38 0.50
0.26 0.50
0.06 0.t9 0.3I 
0.29
tt.t1 a.27 0.27
0.02 0.04 0 13 
0 -38
l):0.002. P(I.{TDa Reginren 5) =0.031: TTL
l)"""0^0J6. P(MTD.: Regiuren 5) =0.018' I'tL
IJ =0.000?. P(lv{TDi Regimen 5}:0.082: TTL
0.12
0.a7
0.35
= 18.30.''o
= 20.2orb
= 15.9 o.,'o
0 0{)
0.00
0.00
fcrr lst scerrario
lirr 2nd sceuat'io
for 3rd scenalio
Table 3 shorvs that. on ilverfise. lve expect tcl rleat ld-lg patieuts aucl6trserve 3-4 ilcicle,ces
of DLT (x16'7-2?.vla) rrncler the tlu'ee tr:xicitv rnoclel scenarios. The uraxiurrun uruulrer of
patieilts irt the stucly is J3 ('6*$+6) if 6 patiellts are rxed in all the close r.egirnents.
Table l6: Er
ted urunber of
aud DLT iucideuces at each close
Drise level (i)
Total
(.q6)
II{TD tbr each dose level
Scenario I
)t)
I*
.:

Protluct:
r
8.5 P(DLT rrt di)
E(# of patieuts)
E(DLT incirlences)
ffi
I
8.6 P(DLr at di) I
E(# of patients)
E(DLT iucidences)
8.7 P(DLT at di)
E{# of patients)
E(DLI incidences)
0.05
il.:
0^01
0oIi
"1 1
0. l5
.{. -5
0.67
0.24
4.0
09{
0.36
?.4
0.85
C conridtntirt
0 -50
0 7 
15.8
0.37 
i.t7
(10 II
050
0.4 
14. t
0.: I 
3. 19
(.22.7)
050
:0 
l8 I
098 
303
{ 1 6.7)
u ll
07
0.08
0. 1.5
1.6
0.69
0lI
4.0
0.8.5
0.06
38
023
018
2.9
0.80
038
1.5
0.56
0.16
4.4
I l3
0.03
0.i
0.00
0.0-r
-1.4
014
0. r2
4.6
0.55
9.0 LABETII$G, PAC:IidGING. STOR-.!,G[ AND RITI.IRI{ OT CLI}IICAL
SUPPLIES
9.1 lnvestigntionalProduct
The iuvestigator shall take responsibilir-y* tbr ancl shall take all steps to uaintain appropriate
records aud enstre appropriate srqrply. storace. harrclling, <listributiou ancl -isage 
of
iuvesligational prodtrct iti accordance rvitlr the protocol and anv applicatrle larvi alcl
regulations.
clinical supplies will be prtr'ided b1'lrterck as srumnarized in Table 7.
Table I 7 Product Desr.l il.rtrorrs
Prorluct \:rrtre & Potencv
Dosrge Fornr
Peurbrolizunurb .i0 rrrs
Por.vcler fbr Injectrorr
SoIutiou for hr.jer.tion
Peurl:rolizulrab I 0(t nlsr' .lurl _

r
ar., I
C (onfidsnrta,t
9.2 Packaging antl Lrbeling Informrtion
clinical supplies ivil.l tre ttlixecl rvith a cliuical label in accorclance rvith regulatory
rcqnirerueuts.
9.3 ClinicaI Supplies Disclosure
This trial is open-label. theretble. tlte subiecr- the trial sire persourel. tlre Sponsor and/or
desilnree ale not blincletl to treatrneilt. Durg identifl, (uame, str:ength) is inchrdetl in the label
text: ranclolu codeidisclosure euvelopes or lists are llot proviclecl.
9.4 Storage nnd Handling Requirements
Clinical supplies must be storecl in a secme. limited-access
conditions specilied ol iire inL;el.
Toprntectprivacl'. €\iell Ir'rlsonirble et-lort rvill be macle to plevellt rurdle access to subjects
chuing tlte cou'se t"rltlte :ltttlr'. All l't'search lelated inrelactions rvith tlre partir-ipalt r.vili6e
locatir:n rnrder the storaqe
Receipt and dispensing of trial medicalion rnust [:e recorclecl lry an authorized person at the
trial site.
Cliuical supplies lllaY not bt-' used for au,v plnpose other thar that statecl in the protocol.
9.5 Returns nnd Reconcili:ltion
The investigat0r is t'elpuustble lbr keepinu accluate lecolds of the clirrical supplies receivecl
fiarn tr'{erck or desi$tee. tht-' atttouttt clispensecl to aud rehrmed try the sutrjec(s *oa Ur" amoult
rernaiuing at the conclusiorr t.,f the trial.
Upou cr:utpletiott or ter:liittaliort of the studl'. all uurxecl arrcllor partiallv gsed ipvesligalio,al
product rvill be destroved at tlte site per iustitutional pc,licy. It is ihe lnvestigator's
tesponsibility trl arrnrlge lor disposal of all eurpry'contailrers. providecl that proce6ures for
prsper disposal lral'e beett establishecl accorcliug to applicabie federal. state. local aud
instihrtional gtrideliue.s artd procedur"es. aud prcvicted thaiappropliate recorcls of disposal are
kept.
10.0 ADS.{INISTRA.TIYIT,l"ND REGL-LATORY DETAILS
l0.I Confitlentialifi,
The PriDcipal Inlestigalor rl'rll ellstre that subject privncy and c6nlicleltiality r:f the suliject,s
data r.vill tre maintainecl
t?t)
i\ 
I l

li:l'"ffi,Hut5o:ro
C 
Contidqnrlat
cotttlttcted lry tlualilied tesurttclt staff nlto are clirectl-v involvetl in the conduct of the research
snrd-v.
To prolect cr:nfideutialitr'. srrl;.jr'ct fil*s iri paper lbnnat ivill be stored iu sectu'e cabinets
tuttler lock arrd kev accersitilc ouly br tlte research sraff. Electrr-rnit l.ecortJs of su$ect clata
wlll be rttnirttairtecl usitty rr il*,licaterl ri'eb-access seclue clatabase. rvhich is houseti in an
eilcrlptecl aridpass*,orii ll'r,t*cted sel\er behurd,h.f 
tireri,all. Access to
electroric datablses rvill lrr linrired to dg1*u,lr*,i p.-r*.l-i*-Ti!Giiiiiy a,t{ r.,iability of r5e
8l
- - -'-"'J
IT ilrti'astflrctule will be rrrrirrirriecl b-v tlr.'t)ilice.if Iir,rrron Research Sen.ites Bioirrtbruratrcs
team aud
I'f deparrurent.
Upou corupletiol of the strtclr'. reseat'clr records rvill be archivecl aucl hanclled per ilstifutio*al
polici.'.
Sutrje$ nfirlles or identitlers *'ill not be userl iu repofis. presentations at scierrtific meeti'gs.
or publicarions in scientitic .jotrr.nals.
10.2 Compliance witlr I inancial Disctosure Requirements
The Prirrcipal hrvestigator irttcl Sutr-Irtvestigatol's rrurst coruply with applicable fb4eral, state^
and local rcgulatiolts regarduru reporling ancl disclosru'e ,rf conilict oi interest. Conflic(s of
interest uray arise f}otlt sittrltruirs in ivhrch tinaucrial c,r othel'pelsorml cousicleratiols haye the
poteutial to contproutise or l,ils l:rofessiolal lgclggtent anfl objectivir;,*. Colflicts of interest
i[clude but are not lirnited to loyalty c,r consultirrg fees" speaking horiorar-ia. aclvisory boarcl
appoirthuents. publicly-tt aclcd or privateh,-helcl equities. itock optiour. intellechral pl.operty,
aud gitls.
The
\.lewSaneltIIattlt',,..\l(seflrch-lc,latecicclrttJictsofirrtei.e@r
Iirb-hr"'estisators tttttst rrl)ol't corrllicts of interest amumllv anclrvitlur j0 clavs 6f a
developed in coujrurction rvrllr rhe
applr:vecl b,v the IRB,IEC
10.3 Oompliance rvith l.ur..\urlit nnd l)ebarment
By signiug tlds protrtcol. rhc irrr,estigtrrlr.ilslees to coucluct tlre trial iu an el}cien( aucl
diligent maluler ancl iu Confoy,,,oo.e vu,ith this protocol: generalll..accepted stantlarcls of Goocl
ClinicalPractit'e (e.g.. Intentrrrional ('i',rrfg1sr,.* nn Harmonizatiol of ieclurical
Requileruetrls lbr Regi:trali,rrr oiPhrlur:lceulical: tbr l{ruuan LIse Goncl Clurical practice:
Consolidated Guicleline lirtl rrther generalll,'ilcceptecl stanclarcls of good clinical practice): ancl
all applicable l'ederal. slltc rir([ local lrrrr,s. nrles ancl requlatiorx reiating to the corrdtrct of the
clinical trial.
i.l

Protluct:
r
C 
Confidsntial
ry'.}illll:|:ll:.1l*1i''.,]lvltlt.ilttclbepreparedr,l.r
tlre piritoiol rilTiffir,, r
_
Ilr.' rrr'estr€lator slrorrlcl rrol i*qrleruer]r ar'der.iaTion ffilo
r'(\'rc\v aud docuurerfed approval;favoratrle opirrion fi-our the IRB
ri'lrrlc necess&ry to eliurirrate au irrunediate hazarcl(s) to sluclv
of an arnerrdrrrerll. exct:pl
sutrjects.
If a deviation ot chRuqe to o protocol is iurpleruentecl to eliurinate au iuurrediate lmzard(s)
prior to otrtaiuing IRB apprlor nl'favorable q)pinion. as soon as possit:le the clevration or
chauge rvill be sulrnritted lt,:
o IRB tbr revierv ;tttcl rlilrrr.'rvali faygr^ble rrl)intorl
a
r Reg*latory A.tlr.r'in lies). if required bt, l.cal res.lariorx
Docrurrelrtalitrrr trl'itr)l)r,,\,rl .r,:rrecl bv lhe chairlrcrrtrrr trr.tlt,signee ol-the Ittll(sr If (.(r) rurrsl
If an anienehnent srtlrstattlr,r]1i ,rlters the shrdv tJesisn r:r'increases tlre poteprial r.isk to the
subject: (l) ttre cellselrt tirnrr rrnrsl be revised ancl ,suburjttecl to the IRg for revierv and
approvalr'ihvorable opiurou. i:l tlle reviseel forrn musl lre usecl to r:[:tain comeru troru
sutrjects cull'eiltlY eu:ollecl in the shrdy if the.v rre afTected by tle aurendneut; a,d (-3) the
new fotll. uttst be tnecl lo ilrt;rru coll$ent ti'om ueu,subjects prir:r to eru.olhuent.
If the revisiott is tlotte t'il rttt lrlntinistrative letter^. inl,estigatorii u)lrst ilrtbln their.IRB.
The investigntor also agrer{ to 1l[6r, nionitoring. audits. IRBiERC revietv ancl regulatory
authr:riry* inspectiott ol tlinl-relntetl dr:cunteuts anclprocedrres aptl provicle for itirect access
to all trial-related solrce ilatr rnd documents.
fte i[vestigator iigreer llol 1r] \eek reiurbrutemeut hour sulijects" their i1slra1ce providers or
fi'orn govenunent lx"osriulri lirr procet{rres inclutied as part of the trial reinitrursecl to the
iuvestigatr:r by the Spons,.rr
The investigator shall l)lcpiltc' rrtrd nraintairr courplefe and accru'ate llial 6ocurleltatiol ,r
collpliartce rvith Ci,:od ( lirrrcrrl Practice stanclarcls ancl applicable t'ecleral. state and local
laws. lrdes and regnrlations. iirrrl. for each subiect participating in the trial. provicle all clata.
and. ttpott cotttpletton ol lL'nnuratiou of the clinical trial. subirit any otherieporl5 t<: tfie
Sponsor as requu'ed b1' tlirs l)r ()tocol rrr as otherwise reqtriretl purstrant to auy agr.eement r,vith
the Sporxor.
Trial docrunentatiou rvill lrr, llr rrtnpthr and fully' disclosecl to the Sponsol t y the investigator
upor reqtlest anci also shall lrc ruade available at the trial site upon request tor inspecti6rr.
copying, revierv nnd arrrlit nr ir.ilsr-)nable tiures b}, representatir,es of the Spousor *.or;-
regtilatory authol ities. J'ltt' tttr csfiqator aqr-t,es lo promptly rake au.v reasoual:le steps that are

ffiffiiilF*ur\o:I,,,
G tonlidmti*N
reqrtesteclby the Sponsot rln ri tes[ltof nuarrtlit [o crue clet'iciencies in the trial clocrunentatiorr
and worksheets,'citse l'e1)irrl lii1111r. The ilvestigator tuust urailtail cclpies gf all
docunetttatiotl ardlecot'cls rrlrrtinEl to the con<hrct of the trial iu.oropli*,"* with all
applicable legal a*il resttllli,tt'requirernents. This docruneuratiou includes. but is uot limileal
to. the protocol- rvorksheets case reporl tbr:ns. aclvefiisrng tbr subject participation. aclverse
event reporfs. subject sonlCc clata, conesponclence with regulafort ffutl-lorities ancl
IRBs."ERCs. consert fbnrtr. irrvestigafor's cruricula vitae. iuouitoi' visit logs. lalroratory
reference ratlqes. laboralot'r cerrification ol qualitl. coutrol procedtues arrtl laboratory
directol cumictrluttt vilae. Ilr .iunilrg this prJtocoi. the inveirigator agrees t5a1
documentation.shall be retilirre cl unril at least 2 years atler ttre iast approval of a ruarteti,s
applicatiorr in an IC'H re!,rori i,r tuttil there are rio pending contempLied marketilg
applicatio0s in au I('H teerori ru uutil at leart 3 years have elapsed since the tbrual
discontirttration of clinical elelc'lopment of the ilvestigatronal pro6uct. Becarue the cli,ical
developutettl aucl rttarkt'tirrc ,rlrplicaliou prr-rcexs is variable. ir is anticil:ated tlal the relentiorr
period can be up to l5 )'€illr ,rr longer atler protocol database lock. The Sponsor will
detenuirre the mininrttlll I L't.irf r.!Il periocl anel uotitt, the irrvestignt6r rvhen'clocullle1ts mn-v lre
deshoyed- The Sportsor ri ill ,leleutdne the ruiuiuruu retentiou periot"l ancl npor request. rvill
provide cttidance to the tttv*llsator lvheu docurnerlfs rlo lcrrrger neecl to be retairrecl. T5e
sporxiol'also recogttizes llial tLrcullrcut$i uurv need to lre retairiecl lbr a longerperiod i{
required by local regulatr'rtt tccluirernents. All tdal cloc-unents shall be nracle available if
required by reler.ant resulalt,rr. authorities. The irl.estigat6r uru.st consult r.vith aricl o[tail
wdtteu appror"al bv the Sl,)i)r\()r prior to destroyiug trial aucllor spbject fi|es.
ICH Good Clinical Pt'actict' srricleliiles recotuueud tlrat tlre investigalor iutbnu the sgltjecl's
pritrrary physician aLrottl tltc :rrb.iect's pafiicipation iu the trial if the spbject 5as a pr.i*ian.
physician ancl if tlte stttr.lt-'cl ir!r ees to the priruar-v phvsicran being intbrrirecl.
Theinvestigator u'tll prt,ntptlr ilfonu the Sporsor of auy regulatorl ardrority iuspectiou
couducted lirl this trial.
Person"s detrarred llont cotttlttutirtg or rvorkurg on clinical trials b1,any court or regulato*
authoritl'rvill uot be alltrrvcrl lo conduct or lvork on thrs Spousor's tlials. T1e i,vestigator
will i[Inediatel.v tlisclore' iti tr lrting to tlie Sporsol if anl, person rvSo is igv.lr.ecl irr
concluctrng ltre trial i-r <lrlrtt t .',1 or if anv prr:ceediug lbr detrannerrt is pencling ol.. to fhe best
of the inr.estigator''s li:t,.rl, It,Ise. tlueafeuecl.
In the event the Spousor ptettrttrrely teruuxafes a particular trial site. the Spo,sor rvill
proruptly notify that trial rilr' . IRB.
10.4 Cornpliance with I'r'ial Itegistrntion and Results Posting Requirements
u
Under the temrs of the litr,,rl 1111,1 Dnrg Adrtriuistratiou }r.foclenrization Act
Fooel and Dnlg Aduriur\rrirlr,,rr .tureuchnerrrs Act (FDAAA). the spousr:r
resporlsible lirr detennirrittu ii lt.'ther'lhe h'inl nucl its resrilts a1e slbject lo
{FDAI\'LA,) anclthe
I

%r,,,flf 
0
f 
Gonfidrntitl
sutrmission to the Clinicitl I t rirls Datn Bank. http:lllrvrv.clilicaltrials.gor,. Inlirmratio, postecl
will allorv sul:jects to iclerrritr potentialll,appiopriate rrials fcrr theiiclisease conditions and
plusue participatiolt [rY callrrru rr ct'ttttialcotttacl nruntrer tbl tirrther infomration on appropriate
trial lor'ations and trial srtr' (\,ltilcl inlirrrnatir.rn.
10.5 Qu*lify Mnnagement Svstem
10.5.1 Dat* Safety Commirree
The Rufgers C'ancer Institutr llurrral Research Oversight C'ouunittee is responsible fbr
arutual data and safety lttorut(,r'urg of DUHS spon^sc,r-iirvestigator phase I airA n, therapeltic
inteleutional snrdies tltat rl,, rtc,t hn\re an ilclepentient Data iafeq,: Ir{o,itoring Bo:rrcl 
-
(D:SMB) The priurary ll',crr, ,rl fhe HROC' is review of satbh, {ata. toxicjties irncl ,erv
infonrtation tlurt may at'lect orrtriect safety or etlicacy. Auggal sat'ery'reliervs lrrct,,a"s Uut
rnay uot [:e lirrrited to te\,i1.\\ ril'salbg rlata. eru.olhueut slatus. stopping nrles
if applicable. accnml. toxicitrc' refbrence literatrue. and irrteriu *rutyrer as provideti by the
sponsor-intestigator. The i{ltr )(' in concert ,*r,ith the eualiry, Assurarrce L.Ionitoring Teaur
oversees the couduct of Rtt{uet i CI}I"J carrcer-relaterl. sponsr:r-investigator therapeiiric
iuteryeutiort ancl prevetllt\)r1 rtrlcrveutiou sturlies tftat dri uot have an extemal uroiritoripg plal,
enstriug subject safery nttcl llrirt the protocol is ccucluctecl. recordecl anrl reportecl iu
acc-orclalce rvith the pl'ot(rc(,i 'rnnding opet.atirlg procechu.es (SOps). Goocl Clinical pracfice
(CCP). and applica ble r.e gr r I i r r,rr), retlriirenrents.
10.5.2 Monitoring
I
The
Qua li[.' Assru ance lr.{orritortug
Teattt rl,i
uil to .nr,u.e that the prcitocol is
condlrcted. recolded. flttd tr'rirrlcd iri accorclance r.vith the pi'otocol. stauclarcleperafirlg
procedttres. gooel clinicrll l)r ir\'llci:'. arci a1:plit:atrL. regrrlattrrv reqrilleruelts. .\s specitie4 i,
the Rutgers C'INJ Data arrtl \rrtctv lr,{olit6rrlg Pla1. ifue qlatiry'Assglance N..I61it6rilrg Tealr
rvill conchrct loutine ulolrll()r rrrs illier the third subject is eruoliecl. tbllorvecl by aruural
uronitor'ing of I * 3 stttr.lc'ur, rrrrtil the snrclv rs closecl to eruollurent afid subjects are no lquger
teeeiving snrdy interr,eulirrrlr tlrrt itrc nri_rre tlran nriuirnal risk.
The
lvillpertbr:n arumal
it1'Assurarrce lt{o,iforlrs TErru \.isrt anel adtiitioual sat'eri,
Prirrcilie I Irrvesrigattu .
Aclditir-rnal uronitcrring u rr r
tiequelc-v crl' serious iln(l , rr
ij'orrr ruonitoring visits. rmex;rer-ted
other coucerls ancl rua1. tre initiated
up()n request t)
. tlre Hruuarr
Itesealcll (.r\ctrt9lll ( (,ru:rrrilr.r,(tlR(X r llic sprrtrr()r . lhe Plirtcrl>al fitr.Ciiigatol . t,r lfie IRB
All studl,docrunents mrr,r bc rrrilcle ar,ailable rqrt-,n requesf to the DC'I lv{onitonng Tean mcl
reviervs on lincliugs ti:oiiill;
and toxrcin'clata submirru,i i
other autltorized regrrlalor.r ',,,,1,,',,"tir:s. inclrrrliug ixrf not liruite<{ to the lialioua

Health. Itiational Cnucer itr:rriirtc" arrcl the FDA. Everr
maiutaiu cr:rrfidentialih. rlrrr rrru,tuclv nronit,rring.
r
C 
Confidon{int
reasouable ellbrt will be mrde ro
10.6 Datn l,{anlgement
The policies aurl ploc€tlrrrr-,:
Handtrook) rvill goverl l,rrl,lr.
be sutrurrtterl tbr prrblicnl li,rr r l
of Nerv Jerxc'v PI. and all ., -,
nanuscript.
10.6.I Stutlv Documentrr t ion
The electronic CRF storetl rri
stucll,. The C'RFs rvill be rrlrilr
data. Onlr, fhe kel"persorrrrcl
make ertries. chartges. ()r (,rr
depnltulent (see: hrvestigator's
tet'ral.-Tars expected that rhe results cif thrs tr.ial rvill
nlrrrller tirIlou,iug the couchmion. The Cancer Institute
rior ti, suburission or lr.se. rrrrrsl levierv anv absfi.act or.
ill ire the 1xirnarr data cr:llectiorl (locuulerrt for the
Ielr nritruter tbllorvrug acquisrtion of nerv sollrce
ou the cteL.gntu:n olautlioriN log are per:uittecl to
tire ('ltF
rr tinrely.
rrrlhor^s pr
Studi,'docturterttatiott ittcltttlc. lirrt is rtof lir:ritecl to soul'r-e dt-rcrunents, ca.se leporl l'onrs.
molitorins logs. appoinltrtrtir seheclulex, strrdv teaur corr.espoudeuce rvith Sponsor or
regulaton.trocliesicorulrrrllr.r.,r, irlrrllegulatt,rl,clticrurrents that can be fclrmcl irr the DC'i-
mandated "Regulatiiry IJirril,-'r '. rvhicir iuchriles llrt is uof hurtetl to signecl protocql and
amendulents. approved atxl 'tsued intirrmtcl cotrsellt firnnr. FDA Fopu I57?. CAp ap<I
CLIA labolatoty cel"lif'tcitti,rus. irud clrlical supl:litr rc.ceiptx aucl riistr.ibution records.
Sout'ce d(lctttlients at'e onr,illritl recorcls that coutaiu soul'ce data. u,hich is all urtbr-nmtiou rn
origilal tecords of cliniclrl 1:rr,.lrirss. rrlrserr.;rlrous. or other actn'rties in a clinical trial
necessal\ tirr the tecoustl.ltclrirrl ;1r,r1 et:aluation of the trial. Source clocrunents inclut{e but are
nclt linritt",d to lrospital lccrrrrl:. e litricrrl rrncl irlt]cc" charts. labcrratorr notes. nrernor.ancla.
subjects' cliaries or e\.alulirt 'rr checklists. pltnruacy clispeusing recor^cls" recordecl clata li.orn
autourated itrstnuDents. ulprc: or trauscriptions certitlecl atter veritication as treing accru.ate
copies. ruicrofiches. photiiemphrc neqalives^ nriclolllm or masuetic ureclia. *-ru,ui. sul:jecl
files. arrd records kept at lltu lihrnnact. at rlrc. laboratories aucl at ruedico-teclurical
depatlutettls tnvolved iu llrt' 'lrrrical tnal. \\'lrrrn po.ssit:le. lhe orieiual record s[oulfl be
retaiued as the sotu'ce drrcturrtut i{ou,ever', n photocopy is acceptable provicled tlut it is a
clear, legible. afld nll exfle t iiuplication of the orrginal tlocuuent.
10.6.2 (f ase Report Fornrr (( tRFs)
, Ielegatecl
l ictions iu
An auclit H'ial rvill be rrtiirril;rrueil uutrruiirlicallv Lrr.' the electronic C'RF nlanageureut $ystem
All users of this svstem \\ lll ,-.{}llrl)lcte llset.training, as required or apprcr;rriate per
regnrlation"s.
I0.6.3 Drrtl }lan:rgemctrt l,r',ccrlurel nnd Dntn \.erilication
iiNll'r li

r
\o.I,',,
C 
Conlidoniia)
Users of the electronic ('ltl' * ill ln'-,e access based on their specific roles in the protocol.
Cornpletertess of errleretl rlalrr u.ill be chc'ckcd autoruaticallv by tlre eCRF systeur, and users
rvill be alerled to the pre:crrut rrlclata inconsistencies. Additionally. the data rnauager aud
project rnanager rvill cro's-re l'elertce the data to verifl acclu'Rcy. \,fissing or implatrsible clata
will Lre highlighted tbr thc PI reqttirinu ap1:ropriate t'esponses (i.e. ci:ntimration of data.
cotrectiott of data. colltplr'li(1u ()t c(rnlhrrlation that data is not available. etc.).
The datatrase rvill be r€\'r,'\\',;rl artd cliscusseilprior to clatabase closrre. aud "vill 
be closed
ouly after resolutiott of all renririnin{ queries. fur autiit trail rvill be kept of all subsequerrt
changes t0 the data.
I0.6.,1Stud.v Closure
Following completiou of tlrc :tuclies. rhe PI rvill be responsit:le fcrr ensruing the follorving
activities:
- Data clarificatiorl fllld,t,r l t- r,rl111isl1
- Accouttltttg. recottciliitllrrll. 11111[ deslnrclirirr retunr oI rxerl artcl uuuse<l
- Revierv of site shrdy 1gs,11rlr lbr c,-;urpleleuess
- Shipurerrt of all relrairruru lirl'roratonr sirrrrples tcr
strulv dnrc.s
the clesr gnatecl labora(ories

Producf: f
Protocov.ffiIll?ut \t,.' I 
u
1I.O APPINDICES
11.1 ECOG Perfornuncc Srirlu\
Ciracle
i )uc(ll : t'ti',* ii.. 
.
',r' ,/r.r.r/("ri1'..{rr.l{e.s3roir.sr, ('t'fer.in Ol'The Ea.ttern Coo|teturite Oncalog,
.',,'u..^i.i, ,r{'r,!.'. The Eastenr Cooperatite Chrcolog-v Grorrp. Robefi C'ornis
ll.2 Conrmon Terminologv Criter.irr for Aelverse Events Vl.0 (CTC:AE)
The descriptions attcl qmtlilr scllt's liruurl rn the reyised NC'I C'6rrunol Temrilology Criteria
for Adverse Everrls (( l( r,i 1 i*rrron .1.0 r,vitl be utilized for aclverse evenf reporting.
(http:/iclsp.ciulcer. qo\' r.el )( 1 I i r r r q r r c. I r t nrl,l
88
NorrurrI aetivitv. Fullr. active. able tcr carl\.
C 
gonfideniirl
pre-drsease
strer]uOus
a light or
self-care
Svrlrl)l ,nls. lnrt ambulatorl'. Restricted in physically
ilctllli\ hill ilttttrttlatory apcl able t0 cflltn' o*t rvr:rk of
I ()()'' o i,,.'iI iiiiL.rr. Clorupletely disalrlecl. C'aurot canv
J'ot;rlli utrufirrcclto becl or chair.
ht l,etl .i0oo olthe fiure. Amtrulaton'and capable of all sell'-care. trut
tutiti,lc lrr cill'ly out ;u.lv wr:rt actir.ities. Up and alrt'ttrt urore than 509o
0f iiirkrlrg lr,,rus.
In bc,l i{},,,, ;i'ii* li,i,e- mp.btetrt "rtl,t"rrlterrcl|.c
to bctl ,,t cltrtir tttore tltan 50o'o of rvaki,s hours.
* As publiihed in Anr. J. ( Iu r
*IcFallen, 8.7., Cttt bot:, i
Gtottp. "{nt J ('lin ()rtt,,
0
I
1
-1
-l
t{.D..
('hair
f)eir,l
litpgugs.:

5\r,:f(i
C 
Confidontial
ll.J Responrn [r,nlultion Criteria in Solid Tumorr (RECIST) l.I Criterie for
Evalu:rting Responsc in Solirt Turnors
RECIST v,.'t siou l . l * rvill bc txed iu this rttrcly for assessurent of trurror response. \ilhile either
CT or N{RI rnay be utilizccl, rr per REC'IS'f l.I. CT is the pret'eued iruagin.u teciurique in this
shrdy.
* As publisheil in the Eur,,lirirn Joumal ot'Caucer:
E.A. Eisenlrttter P llterasse,.l. IJogaerts. I-.H. Schrvartz. D. Sargeut. R" Ford. J.
Dancey. S. Artnrck. S. Ciu r ther'. M. Mooue),. L. Rubinsteiu, L. Shariliar. L. Dodd. R. Kaplan^
D. Laconibe. .I. Veru,eil. Ncri' l'e$ponse er,irluatir-lu criteria in solicl fluuors: Revised RECIST
guideline (r,elsion l.l). I:ru .i Caucer. ?009 .lau;4,5{l):328-47.
In addition. r'i:huletric irrrrl',:is will tie r,splorerl lrv ceuttal revielv tbr respolse assesst]]et]t_
11.4 Events of {llinicnl I ntrrest Guidlnce Document
Please refer to sepill itl. docurnent.
11.5 Processing and Shipping of Tunror Tissue antl Correlative Science Blood Samples
*NOTE: Partjqpalgu {crrlr'ti ivill not tre }rlocessiug speciutens locally. All sarnples rvill be
*li[il,ffi il:r;:t#uf, nTi[:nr*il:;'Tri':r*****
obtai[eti ancl ruust be t irr:rrclrtea tcf 
\\hen tluuor ant"l bloocl are cr:llectecl on the same
day, they lnttsf be shipl:ed ti,cether at 4o(' Please ret-er to instnrctiou sheet ivithspecimerr kits.
11.5.f Tissue Collection
ll.5.l.I Collertion ol peripheral hlood
a^ Pelipheral bloi,ii ir rll be collectetl bv venil:uncnu'e irrto tbur veuous blood collection
tutres (t'orir Gt'e.'u i''rp tubes with sodiunr hepariu: IJD vacutainers catalos# 366480).
b. Tlte saruple rvill l,e trausporlecl at roour ternperatrue (18"C: to 25"C) iu a double
cr:tttrrittet'tt'oru tlr.' collectiou site tr: the sample processirre labor:atory.
c. Green Top trtlre' 1.rr p*rip1r"ra] bltrod urououuclear cell (PBM(I) prt"rcessiug shotrld
be kcpt (ltt il l\rrl\cr at rcom lr'lnperatlu'e rurtil processed (to avoid cloltiug) and
prr-lcessecl it.y sr)rrll ar possible trvitlrirr;l h urilriruurrr) aller bk:t-rd colleclion.
d. The collectit'rrr lrrl.res rvill lre labelecl u,itli the patient ID. date. ancl fime of venous
U61,ql d1n11,
e. Sarrlrl*s rr,ill bc hurclled one prtierlt af a tlnle lo ar.r:id urix-ups.
r

ffi.o.,r{)
S Conltrtmttrl
ll.5.l.l Clollection of tumor tirsue and handling of archiyatr tumor tissue
a. Fterlt ttttttol tis*tre will be collccted by biopsl,'arrd ruuuersed (completely) in sterile
colti tl-7"C') }{BSS in a sterile'specimeu cup (tbr exarnple. VWR catalog# 15704-
088) orr ice (tare rutrt be taken to rrot inunerse the cup/tissrm in ice to ar"oid freezing
the tissue).
b. Tlte specilnen cup will be latrelcd rvith tlre patient ID. date" and tiure of tumor tissue
cr:11cction.
c. TItc sarrrple u,ill be ftansportod on ice h-our the collectiou site to the sarnple
prt,.,..'.s i r rt lrtruratoty.
d. Tissrre processiug should be d,,rre as seou as pr:ssible ailer biops-v- (and u,ithin 3 h
maxinuun) alier tissue collectiou
e. Saurples u,ill be haudled orle patieut at a time to avtid mix-ups.
f. At'clrii'al htntor tissue (for exanrlrle. in paraffin blocks or pathology slides) shoulcl be
kepl ;rl roonr ternperatru.e urtil ;hippinu.
1f .5.2 Tisrue Processing
11.5.2. I l)roce ssing of periphersl blood
a. Cir r.'n I r-rp fubes rvill be prncessed as lbllows:
i. 
Cirer'rt Top trrbes will be rurxecl [r,v irrverting the hlbe geutly 6 to I tirnes.
ii. 
LIp to 10 rnl of peripheral blood ivill be added to l0 url of PBS in a 50 rnl
Frlcou tube artd urixed l;v inverting the nrt:e gently 6 to I tiures.
iii. 
'l-he :10 rnl peripheral bloodiPBS uuxhre rvill tre overlayed try slow carefirl
pipettirrg orrto a ?0 ml laver of Ficoll irr a 50 rril tube.
iv 
T"lie peripheral blood,l'BS.'Ficoll tutre rvill lre centritirgated lbr 20 ruirr at
I i.<0 rpm at roorn teurpelature tvithout the break.
': . 
{lstrrg a transfer pipette the clear top plasrna lay.'er will be r"emoved and
rlircarded as biolcgical rvaxle.
li. 
{ )sirig a nelv trausfer pipette. the cloud,v* PBN{C' layer rvill be trausfbned to
n 50 url conical tr[:e.
vir 
(.'lt(. rmtst be taken ltr,t to clisntPt
l,l rrrilg eeutle piperrrnu ilt:olc.
liilli)llitry.
lr, 
'l lir cells rvill be colrlrlt-rl {rrsirrg a
the errlluocvte la1'er du"ing the tlarxfer
tlre Ficoll la\,er aud keeping the nrbe
stanclarcl lreurocvtoureter) and the total
e r'il cr,rrmt recordecl.
r:;. I'll5 rvill be added to tire PBMC' nrlre up to the -i0 url rnark and the hrbe lvill
l;c cu'rtttjfitgated fcrr 5 rrin at 1750 ri:m af rr)rrul leluperaftlre rvith the lrreak.
):. 
I"lre sttpentatant will t,c cliscardecl and the pellel dissolr,ed in Cr-vopleseme
",,lrttiotl (l rnl Cryoplcrell'e solutiol per I rnl of blood) aud fransf'ered to
L t\'()f ials (l rnl per cn ovialJ. The cell cc"rucentraticrn aucl solution volunte
,' il ire recortlecl.
. 
',..i rrliquots will be pl,rucrl ulitiehl in
e rtlrrlrrq #5 100-0001) ;rl l,,(' lol rry.r lr.r
r
a in a \[r" Frr-rsfr, (J'henuo Screntific
I}ir
2-1 liours aucl theri
I}
i\

Plodrrct: ! 
'
Pt'otocolr.,fiii , rrrlrr , ,r \o.: I 
t)
1i(r'zel' iu a specimett h$\. All speciruens
r rirrl [6 shippitg. The rau4:les shouiclnr:t
11.5.2.: [)r'rit , s.ing of tunror. tissrre
Rel-erertce QI '.\1.1.i:ir littroratr:ry manrnl lirl insfnrctioll on processing antl shippilg of trunor
tissue.
Shipping Trl.llc
91
C 
Conlidentiat
should reulaln at -8ffC or colder
be tharvecl prior tti shippiug.
Storage {before
shipping)
Room
Temperature
Storage
during
shipping
Room
Temperature
11.5.3 Shii,pir
a. Prirx' rr
b.
i,.-r'sorurel rvill be ar,'ailable t'rn the c,\pecte(l clelir.r.n.clate aud tinre.
:ll qenerally lre ar"ail:r[:le to reuells-).lru4rents "l'uesrlilv tluouglr lrlida1,.
'. rnurent holirlavr. Il neeclecl I 
cirn be contacteri ilirecrlv at
J
lce packs
Room
temperature
lDusl be sent to
nntl
tr: adyise the
scltedulecl ;ffins 
Reacl,v tbr'
irr thc subject line. A confir:uation e-mail rvill be tetrured
tu'e recollulteudecl to ship out r"ia FeclEs ou the
tieliven trv l0 AIJ Tuesclav Ferlls Frlst Overtrisht ).
d.
iI !rcessirg saurples
, r r.jav atter"Lcrol for
;lriprueul
i.lrrtgels
Time allowed between
processing and shipping
Shipped same day as
obtained (max <24h)
Shipped same day as
obtained (max <24h)
Samples can be batched
for up to 3 months
Samples can be batched
for up to 3 months
-TIfr', - r,,
furilp1,. ;,1g
Fedl:'r',-'t'
n,&
To 
'rr''
[etlrnr
labels. an e-rnail
cilrt be
to
{processi' rg e r: I lroint}
Bl.od (PBMC: fic,'' Creen
Top tubes)
Tumor (HTS-FRa p,,, i.r*d
from fresh t .:uel
Tumor (forr; lin '
d from
fresh tissuej
blocks or slides)
e
Room
temperature
2-8"C
Room
temperatur
Room
temperature
exchr "
m

r
be lrt ',',
shi
e. Sar, I ,'
C 
Confidr*ntial
i rriui;t be listed ns well as the nrnnber of shipurent labels requested
lrelr r.vill lie pror.idecl withiu 5 brmnress davs.
list cr)nLuning pertinent san4tle inlolrnation shorrlcl lre seut to:
specinier recorcis rnust be uracle so that one cop1.
the saurples aurl oue can be rnaiutaiued at the
irr c;tch palienl tltat ar e shipped rurrlel that sar:re slril:piug coucliliou shoulcl
r i ,,'ri iu a single storagu contaiuer' ( such as an 8 I 1:lace fi'eezer box). Saurples
'irl patients shorrld u'rt tle ruixed in the sulue storase coutainer trul can tre
llte saure slupping cortahler (as lorrg as they are separated iu different
ita irre r s).
't lir tlte Prrst-ptoce.,.irtg artd Shi14:iug Iable tbr' po:1l-processiug aud
'I ri ils
sltilrutent. storasle c(,ntainers r,vith saurples fiour inclivitlual patients should
tlr* :hrppinEt cr:ntaiucr'/s and ihe conteuts oithe package should be ntatched
,irrg ruarifbst. Both copies of the shipping urauifest shorrld be sigued aud
n(' c()pv r:f the shippirrg ruauifest ancl recorcl should tre placed il lhe box.
oultl lre sealed ancl r shippiug label attachecl onto the outside rif the shipping
lhc' cuittairter slu:rtild be latrelecl ns contaiuirrg triohazarctous speciureus.
rirrg clate. tirue, tlrckrng uuluber. urd shipping iutbruratiou should be
;il:,ffiiThe 
'mEiru-urologv L.alroraton, .t I 
rhev rvill be
'l;- lrhcecl at.1o(. (tl",r' ,U,'trorrn-tjxe{ htltor tissle) or -80oC'(6r lorver for all
res arrri Ptsh{('s) for pentling cou'elative science tvork or fbr storage.
tipt rrl'the sattples. an e'ntry will be nrade aud saruple uuurber issued tbr the
satupi.' irt the 'l'ru),,r Inunturologt Latror;rton biospecimett reposilory
Precrr rrf ions
tiottr ti ir.. il lnethorl o1'rnfbctior c(lllttol ip lgfiich illl lttttttan blooclsld bodv
las rf ilrrv ate iu1,,'ti,,rrs fol'Hepntitts Vinrses. I-hunlu rrrrr,
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a. I'i., ,rtis Il rrrd l{epatitir C'r'inrses may be traffimitted tluough blood and otltet'
L:t', l. fluirls uticl ale ass(rtiilted with acute" hepatitis. cluquic liver disease. ancl
hc'1,ri{ocelhrlilr ci,ircinoma il huuraus. The protiatriliry' r:f selotrot}tr'ersion atler
lee,il*stick espo$u'e is estiurated at ?o.b. Lhttreateclvirus cao persist tbr up to olte
rr,r,,,,. at t'or-r111 lgrrrreranlt'r. .Ul staff rvho rvork rvitlt lttuuan ttsstte nlttst prc,\'ide
, ce {r1' l lepatilis B vriccutatiott.
liltox,n aud uuknorvn infectious agent$) will be utilized rvlten handling all
r issuei.
rr Lrrrrrrrrri-rdel'icirntr vinx (I{I\,') is a retri:l'ints thal caltses severe
rnoclet'icicncy. Iufbt'tiol increases the risk of tlet'eloping rnalipurancies.
,iou trr, crpportnistic or sauisrns. and denth. The probability r-rf seroconversion
neecllestick exporiurr. rs estimated at 0.5o,'o. hrfbctivitv ol urttreated virus
.,1s tbl rrl,l to one wecli at room temperanu'e.
r pot*utiirlly irfectirrrs ngeuts. both knorvu artd trukrtowll" pose ltazarcls tt:
workinii rvith lrtutrltn tissue. Incltrded are nrlrercttlosis. HTLVI.
i, I it"ru r vc, rr is. Clreutz t cl clt -.Iacot: ctisease, aluottqst otlters.
,,1tnl iu"lrnrtioual fllti,l (.)SHA gtriclelures mtxt be tbllorved rvhert handling
rrr cells lrnil tissues. rrrcl lefei:ed to tbr aclditiortal ittbr:rratiott on blooclt:onre
,,-:ens" hlrolatory sali'tr. cheurical sat-el1.. and bicdrazalck:trs r.vasle disposal.
...:
r'crst,ual l)rotecti\:e rqurpurent (PPE) ruust be usecl at all tirues rvhile rvorking
.,,,ith lrrrrrrnir lissue. T'hese include clisposable latex or nitrile gloves. face
.lriekl. lrr\)tl'cli\.,e sp1;r.h-resistant laboratolY coat (tiisposahle preferred). aud
covercil lll'otecti\:e slti,r'.
(ilovcs slroulcl tre irrrnrcriiately lemorred anil replacecl irr the event that they
I ,ecorne rr)lr) or pet'li'r ated. Glorres urtrst lre reurr:ved prior to leavirrg the rvot*
i ea. nuil clisposed t.l'iu arr appropriate rvaste disposal corttainer'. Hattds mtmt
be s,lrslrril in ir "cltrrr)" sinlt after t'emoval of gloves.
l,'rrcr slriclci,r. gog(i,'s rrucl masks shoultl be rvout whenever a potential lor
.xposurc to splaslrt,'. spraY, splatter, cL'oplets. aet'osols of blt:od or tisstte
tluicl. or ,rther poterrrirrllrr infectioln rnnterials ntav tre qenerated. arrd if there
r a lrole rrliai for er L.. ltrls€ or mouth contaurillation. The-v shoulcl be rvom at
ll tiurr's rvhile harr,I irs tissue iu tlre lirr pl'ocesslllg.
'r.oir",clivc litlr cr,,, . lirel'eraltly dispr:sat:le t.vpes. nrtrsl be doruled w'ltile
',r'ilrk nrr., *'ith tis;trc. (.crntaminatetl clothing rrrtr-sf be reutovecl prior to leaving
ilre rvork alea^ arril rrpyrrtlpriatel-v lrrunclered ol discardecl. as per irrdivichral
r r rslituli',rral guidelir rts
.', ll ,,r,l.te rnust lrc , rsp,rsed of prior to leavittg tlte rvork art'a. Bioltazardotu
'ltrps rttrtst be pt..,t .'rlr disposed ol il fllt tpPrclvecl "sltatps" coutaiuer. All
,lrcr rri,rr-Shnrp r,, , le nlttst lre disposed of in an approved orailge Or led
i r i r.1ltr I ll |r ltrtt: \viltl r', 1r slrosal bag.
ilicr c,,rnPletiol ,1'uork r.vith lttrmatt tisstte. all rvork stut'aces must be
,lisirrlccieii u,i1lr a Ii')dllcl that has t"reen dentoustratecl to be etlbctive apnittst
\'r

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pr.otocoll.\rrr r'i rcrt 1,,., 8,. 
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conlidt*ntinl
l,;i.--t.riir. r,inrses. l)scu(lomon$s. trtbetculosis aud fungi. Product literafure
',,rrlci lrc rclerreLl 1i' nlr appropriate use.
e. .\il" i ,ttli':s,.,t'c\l,)oslrl- l''htrrirantissrteorpotentiall.v.iufectioustliologicagelts
**,1,1 I r rclrr-rlrecl po.ny,tltr, arn specified. irr irrdivicltml iustitntioual safety guidelines'
Ref'erences:
l. 
Sre, ,l '.' ',i;t .. lLrlt./.. un,l.Tr.llril '\. Cartcer rlittisltcs. l0l'1. C{.' tr ttttrt"er.fottrttul .fbr
t/irt ,: 
-'ili I r, l{Ir:il-l
?. 
Sclrrril.lirir! 
( . \'1ll dcrr I1,,qirr,tt W. Dalesro O. Festen.T. Hoogenhotlt.i. r'an Horttte
p.F,irklrr,rricl. \ Kli,leo\l.Il*rrB,Nr-isA.etal.Eftbctsr:rfcottcotnitantcisplatirtand
racir,rllrtt.,ir', \'rr itt,.ri:enblc rl.rrr-sttiall-cell ltulsl cilllcel '\- Lt'ql 'l '\lcrl'
l99l:-llr I il': -, I -l1l
3. 
Cur, , , 
'. . i'. l'rrrtlrn ll 
T :uru.er C'.T. Korriilki R. Lee .IS. Hattser S' \fol'sas B'
Wl 
, I lt,,.r,rrrlrrtl 'i ,,. (.i6re E. et a]. Seqrrerrtial vs. collclll'l'etll chenloriicliation
for.,,, 
1,,p-. 1rrll cell l,rrr : cuncer:rauclotttizeclpltase III trial RTOG 9l1A' Jotrntal
o./'ti,;' 
)i,,,,',' {,///r'i'r' l'tt'ttittr:,' l0l l:t03(l9}:lJ5i-60'
4. 
Fur.r rs., I i's1.rr,'i.lr \{. (11r,,'11lrr1ir |"1. Nishikarva H. I'ilkacla \'. Ktrdoh S. Katagami N"
al](l -\ri. lri ', i,lrrrc IIl ,trrrlr \rt'collctulerlt \"erius seqrtettttal lltoracic radiotherap;-
itl c , , ',, i, 
..,. ltl, ntilortrvcr,i. r'ntclesirte. attcl ctrlplattn tll uluesectRble stage III nott-
' 
ri,- .:rir.*r. ./ ('!itt thrrol. 1999:17(9):2692-9.
.,,rrlil.i lill.. "l'lr;rrrr.rr HD. Jr,, Liu FIH. Tucker Sl,. lr'Iohan R. N'lallel MK.
,rrr li. Kir:r ES ct ll. Iutluer}ce of'{eclxrologic advances on Crtttcoutes itt
ilit irtrescct:rlrlc. 1,,cx11, nelvartcecl tlou-sruall-cell lturg calrcel' receiving
' 'rr clr,-'rilr,trcliotlit'r'n1',r'. htlefimliottttl,itttmml aJ'rodiorittrt ttttcologl', biologl',
;rr) -'rrillj77-i-El.
r ,. "\r.rirgurl;r lr. illrrrix E. Rullle, P. N.lartin Ir{. I)ouillald.Tl''.'ralal're \"1.
,.irir.r lrl.l . ririri i.irplartclte A. Ratiiotherapy alone velstls cortrbinecl
r 'r'. :*]ti tlirliotl,.'rill)\' ill tlm'eseclfible rton-snlnll cell lung carcirlorna' L1"g
, i ;t) \rrppl 1(Sli1)- 1,1.
i. I i,.'r rrrltrrr .T. Sr,;tut,:n SL. Eiitott WL. Jr.. and Cileell L'{R. Intproved st[vival
ir,,rr,,rrlrrrll-cell lrrrru cirucer': sevt.l)-,vear ILrllo,.v-up olcancel'atrt1 lettkertria
I i( \l(ill) Slrl rnal. Jotuttctl of the Nuticttrrt/ Cotx'er lnslilule.
r l Il(i-'i
i ,.( lx'i lli,-,r '1. i,)rrois E- Rnt'fie P. cle C'r'euroux H. Douillard JY. Tara-vre
, 
:, :1rrl l.ri1,l;1111ir,-, " 
.\STRO(Antericalsocie$ tbrTherapetrtrcRadiOlOW
i-' 'li I 
'lr'llrr\': 
I:il,r.,t ,l'cltentotlret'itp\' oll to"*ii1' atlvarrcetll
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ir'','r,r,,ririr: l tiludorriz-L'rl study clf 353 patients. GETCB tGroupe d'Enrde ef
, , . I ur rc,.'r i fl r , , rr, lriqrres)" FlriCLC(" (Fecleration Natiotrale cles Clentres de
,. ,' , ,ir , r r irc C'EBI trialrsls. Ittlenrttittrtal .i,tttnrtl q/' rarlittiort
, ,' in, ,;,r,t . jr,I \l(.r'. I ') l.l0i6):l l8-l-90.
',". ;.rirrlr: I.\1. l):r1.,'rskaia Ci\'. Seclor,a'IN. aticl Korcltirk A\1 [A case of
1-
rr i. l' i,rl' ' 'r'. Spiotto N'{. I*,ai \-. Honlo T. alid Ciaje*'ski TF' PD-
,:ls r' ,' 
r Irltilse oi'lttttttrL re.lectiott b1'1'cell receptot (TCR)
I i Ir,,'ils ir 
,,i't't,tt,ilt'(lt l(X)J.61(3).ll-10-5.
i. \:,.., lJlJ..ir, , illrssoq, L.\. Pfiaee gtoup ii staphr,loctrccal straius rvith
;i. ,ii,l ,.:tl;rcllt!..r ,\(llllal g,err,js lol estbIative lgsin prtrciuctton. ltlf'eclitttt
tic lrrrlrlr rrrriir in Nepal. T'ropicol urtirnnl lwtltlt aud praductiort-
';liar? LL. Galli Ir{. \\Iest A. Nlclattghlin }iIrI. Druet H.
rli LI.I. et al. Rirclir:rtherapv increases tlte penttissivetess
, r,i to lejectiott bv ittuttttttotttt'rtlttlati:r1' antlbr:dies. C' au cer
i
;.,rrvashirua li et al. Fractionatecl trrrt not single'close
' ,,,,'-rnediatecl abscopal ettect rvlten cotnbinecl with anti-
r Il"es. ?009 Sep lt15(17):5379-88. doi: 10.11"58i1078-
') .\us 25. Publrled P\'{ID: t9706801: Pubirled Clentral
i fuiti-PD- l blockade atld stereotactic ladiation prodttce
,' rlr intrnclanial elioruas. Itrt J Racliat Orrcol Biol Phys.
i0 1016;i.rirobp ?012.1:.015. Epub 3()l-j Feb 22.
, \ k'cl (-'en tr a l Ptr IC'ID : P\ IC.l 96.3'"10,j
il-Ornair ,r. el al. "fhe I37-H I (PD-L I ) 'l' lr'rnphocfe-
' ,'ilst clltcel pattents u'ith irtliltl'ntirrg tluctal carcinoma:
' ;ognostic factors. Ner:plasin. 1006 lt{ar:S(3):190-8.
rntral PN{C'ID: PtrIC l -i78520 I 7
Deng L. Liang
: :-PD-I-l treallrlelll
svnergi stically' prornote
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, .:sl. 201,1 Feb 3:124(2):687-95. doi:
i lr,i, :'Lrh\led PIl{lD: l-1381348: Pub\'{ed C'entral PN'ICID:
, 
I ;ii 
i.te S\'. l{ur['nskr. .\\-. 'frattsietll rc'g.tilator1' T cell
or 
. :r! i 
rr lrr*:,rsl crule rl attcl etiltilrtces racliothelapt. J Estrl ivled^
I I 
I I 
, clc,i: i0 1081 jenr.]0l3076l Epub 2013 Oct 14.
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,r, .,1 , .1. l.r ihii (\1. Nirsclil TR. frattcica $.1. \''elarcle E. Deleese
; : r"." trr,'ic I',rililttott'fliertrpr'-{ugurettts .\ltigeu-Specrtjc PD-l-
,: 
tt 
ilr;prrttst's via ('ross-Presetlta{iott ol Tttntor Alrttgeu'
.,.\(, '.r ',. lttl-,1.
I lr 
.l ( rt', jl i-l intrsdor t' I). Nlcl"aughlin .l- \'elcheti \'. Suigos KN'
i r rr , )i r 
,.1i,,,-. rlrel\slelrlent ancl clinical sistttticnttce of TILs iil
r. ,' r,.'rr , lt ,,iii tt/'lJ1p .1'1,1irrttfil Crttt(t't' ht.stitttte. l()l-l:107(3)"
,l i,, t I. Jirtrrri.'[ 0. FIui R. Cianclhi L. I-eishl N. (iubeus lt{'
i 
'1. ltttettclltritot K" t'l al. -"\trsttitct '\10' IUK-3'175
r 
ir:rv rcrre(l tt,.rtt-stttltll cell lung callcel {}iS('l-C'). Preirminar}
it . t 'r ir'trl ('trttt t'r' Ac.icrirr-/t. l0 l'l
I i rr rr,l I). Slincltcontbe-fE. Dv GK..\.tttottia SJ- Honr L'
'.' l 
r ",'l iil. .\clir rlv ntltl ial"etr"of ttir,trltttttiill. arl artti-PD-l
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1 ,1 ;rlrlitttt:, uitlt aclvattct:tl. teti'itcltlt\ s(lllit1llotls lloll-
lr I ' I;ric ()6j). ir phnse 3" sitlg,le-irrilt tlinl' 1fu2 Lurrcel
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l''rt, -'11 PL. l'ltatchcr N. Havel L. Krzakorvski II. Na$'rocki
r I. ' tgl J\1. c'l al l'ecettttrtitle iL-BLP:-\) verstls placebo
, |' 
ilii'-rc III ttlit-stttall-cell ltuis cl'tttct'r (S-l'AR-l')' a
r , r: ' -r rr irrl. -/7tt' l.tttrt-<'t ()ttcolo,qr' l0l-1.15( 1)l:9-68
I irt 
'\',-'1,.'L.lS- [lrrrlrril(). Lebt:e ('- \lirrt' \I. Biucier \1"
I i r ' , r\' 1{. }Iodr I'S. Gurcielines fbr tlte r'r'alttatiott of
. r .! ,rt ltullrrts. itttttttute-t'ela{etl rcsl:rlttse cnterra. ('lin
I ;(. 'i:7lll-10. tloi: l() ll-iS 1l)?8-(J-{31.('CR-09-l6l-1"
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