Conditions: Recurrent Prostate Carcinoma Stage I Prostate Cancer Stage IIA Prostate Cancer Stage IIB Prostate Cancer Stage III Prostate Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 27
Healthy volunteers: no

Brief summary:
This randomized phase II trial studies how well metformin hydrochloride and aspirin work in treating patients with hormone-dependent prostate cancer that has progressed after surgery or radiation therapy. Metformin hydrochloride and aspirin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving metformin hydrochloride and aspirin together can slow the growth of prostate cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the effect of metformin (metformin hydrochloride) and aspirin on the change in prostate-specific antigen (PSA) progression in men with rising PSA after definitive therapy for localized prostate cancer and stable disease during a run-in period with the study regimen.

SECONDARY OBJECTIVES:

I. To determine the feasibility and safety of administering metformin and aspirin.

II. To determine the effect of metformin and aspirin on PSA levels and the serum obesity-related prostate cancer (PCa) biomarkers (insulin, insulin-like growth factor \[IGF\]-1, interleukin \[IL\]-1beta, IL-6, and tumor necrosis factor \[TNF\]-alpha).

OUTLINE:

RUN-IN STAGE: Patients receive metformin hydrochloride orally (PO) twice daily (BID) and aspirin PO once daily (QD) for 4 months. Patients with disease progression (PSA increase of \> 50% and minimum of 2ng/ml rise in PSA) come off study. Patients achieving disease response (\>25% decline in PSA) continue to receive study agents in the absence of disease progression or unacceptable disease. Patients with stable disease continue on to the randomized study regimen.

RANDOMIZATION STAGE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive metformin hydrochloride PO BID and aspirin PO QD for 6 months in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive metformin hydrochloride placebo PO BID and aspirin placebo PO QD for 6 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12-16 weeks for 1 year.

Arms:
arm 1: Patients receive metformin hydrochloride PO BID and aspirin PO QD for 6 months in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive metformin hydrochloride placebo PO BID and aspirin placebo PO QD for 6 months in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Aspirin intervention 2: Laboratory Biomarker Analysis intervention 3: Metformin Hydrochloride intervention 4: Placebo intervention 5: Placebo
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Given PO intervention 4: Given metformin hydrochloride placebo PO intervention 5: Given aspirin placebo PO

Protocol document:
Prot_SAP_000.pdf: 
Date of the
Document:
Metformin Hydrochtoride and Aspirin in TreatG iliert,
With Hormone-Dependent prostate Cancer That Has
Aflerlrrgery or Radiation Therapy (pRtMA
02420652
Study Protocol and Statistical Analysis plan
0t/1,6/20t9


Title: A Phase 2 Rantlomizecl Discontirtuatiiiu Trial in Patients rvith Honntue-Dependent Rising
Prostate-Specilic Antigen Pr.ogressirrn After. Local I'herap]: I.or prostate (.arrcer fvaluarift the
Synergl'of \{ettbnuin Plus Aspirin (pRIh.fA Trial).
ftt 
f,nder Investigntion: ]rletfcrnuin ancl Aspirin
Funding Sources: I)eplrlment Funrtetl &
:,ixfilllll,;,1T1,1ilil:XJ:,ll;,[',,Xt']l:l-H" ,il,*fiI
sporrsot.'
Sub-Inr estigators:
r..,il


2.
3.
,1.
Title: A Plmse 2 Rarltlo,rizeti Discontrorration Tdal irr Patients rvirh Ho'none-Depeudenr Ri*ing prosrare-specific
;r-ili;1?ffie-ssiort 
Afier Locnl Therapr' lbr Prostare cancer E'al*ali,g the sluerg-v of Ntetfoid, plus Aspir.'i
Or'f
TABLE Of CONTEI\ITS
I. 1 PRn,IARY ENDPohTs.,.,
I.: SEC0ND,{RY ENDpoNTs
1.I DISEASE ASSESSI{ENT.{rTrR RTDJ Ni STACE
.1.: RLIN I\t STAGE..
'......-.,.,.,.'..,.,.'...'-..'..,.,.,.,.,.,.'.
..., -., ' l
t:
..'....'.,.,.,.,.,.,.'.,..,.'....,.,.,.,.'.'.'.'.,.,.,.,.'..,.,.,.,.'.'.'.'.,.'...'........,.,.,ll
4.5 DISLASE PROGRESSION CRITERIA DURING R.{NDO]\,IIZATION STAGE TREATMEN1......,...,. .....I?
{.6DURATIONOFFOLL()\V_UP........... 
.....................1?
5.
.S, I I)iCLLJSION CRITERIq
5.: EXCLUSIoI. I.RITER]A
5.-1 \\,'0MENANDNIL\ioR-TTIES..... ..... ... . ..
...1-1
... I .i
:,.I C.HILDREN
.5. 5 STLIDY Ei$,ot^I,MENT PROCEDLIRF-S. -
6.
10.
ll.
?.I GENTRAL ('oNSTDEL{TroNs . ... ... .....
r.l STrrDy AcElrr... .
?.-l D0sE NloDrrcAlloNs oR ESC...1,LA t IONS...........
J..I C:ONCO[,[TA\T I,IEDICATIoNS
7.5 SuppoRTnr CARE GL,'IDEIINES..... .......,.
?.6ADHERENCBC.0MpLIANCE ,.,.,,.,. . .,. .
:, ? ET.IERGENC'Y U\tsLINDING PROCEDURES .,............,
l(
t5
l1
t:
l?
9.
TOXICITII $tOl{ToRING AND ADVERSE EVENT REPORTII$G 
....................17
8, I .{DvERsE E\E},IT REP0RTLI'.IG REQUR.EME}IrS 
... .. .., .,. 1 8
8 i DEFTMTIONoF SERrous.q.D\ERSE EVENTS(SAES)...,.............. 
...,........,.,..............18
8.d DEFINmoN oF RELATED.{DuER5E Et'Ehrr 
................1s
8.,r DEFTMTToN oF U\EXPECTED ADVERSE E\E:[r........^.. 
................^....1s
TREATMET\T EVALI":ATION/C:RITERIA rOR RESpOtiSE.............. 
..................1e
9, 1 BIO(.HEb{IC.AI RE}PONST. PROGRTSSION:
. ' -., ' '.,, '. '. . l 8
,...' '.,'19
Rfllov{L or PATIE\TS I-ROII STL.D):/(]FI .sTr-Dy c:RITfRLd.. 
................t9
LABOR{TORY fl'.{Lt ATIO\S A.\-D C.ORRILATnf STI:DI8.S..... 
................20
I I . I C0LLECTToI'i AND HANDr^Erc pRocEDLx,Es ....................
1r r
,, ,,,..,. 
. . -1,
9. : CLTNIC:AL PROGRE S S ION
9-i suR\.T'AL............... ....
r2.
Pr.'tt,iul Vc:! .,(,1, S rr l l r ,l lr l -
I
l.
8.


13.
Title: A Plmse ? Ranelomized Discontirnratir:rr Trial irr Patieurs t,ith Honnorre-Dependent fusirrg Prostate-Spec'ific
,\rtigen Progressiorr Afier Lqrcal Therapl, lbr Prostate C'ancer Evalrrating the SS.nerg-l of Mettbmrit Plus Aspirur
{PRI]vLA. Trial).
i,,'I
DATA COLLI(:TION At'iD RE('ORDS TO BE KfpT........... 
...........21
IJ.3DATASL:BM]SSIONTIMELtrIEA.}iDF0RMS,., 
....,.....:I
l.i.,l REP'RTS
I.i.I IRB APPROVAI-S
ft
I i,: OTHTR PRE-STUDY D0CI,:MEN]"IS
14.
15.
16.
17.
I .5..] INITL{.TION \IETTINCS
ll
I 5,.{ IRB CONTL$Ltr\TG APPR.O\ ALS , . .. ..
:-l
15.? DA"TA COIIECION AND TO)(CTTY I{EpORTINC......_. 
......................?3
15.8 DATA MoNrroR$ic AND S0URCE DoCUMENT VERmcATIoN 
...................._........33
I.5.9 DA-TA AND ('ENI'ER AUDTTS
STATISTICAL CONSIDER{,TIONS 
........23
1 6. i OL.rcoME lv-{EASLrRrs
I6..i SAMPLE SIZE AND STATISTICAT. ANALySIS 
..,.,.,:J
11
,!
?.t
I ?. I SUBJECT Popt.I-An0N .....
Ir.: PoTENttAl fusKs . . . . ...
I T, .i C0NSENT PRoCEDLq,ES , . , .
I,-1 POTEN.UAI, BEN.EFITS,.,.,.,
I 7.5 rusx-BENLFTT RA.i'ro.......
I7.6 CiENDER AND IIINORITIES
1 ..1
. t.{
1{
r8. 
ECONO}flC1TINA!(CLI.L CO:{SIDER{.TIONS 
..........25
19. 
P[:BLIC..!TION OF RISEARCH rMDIliGS.. 
..............25
LIST OTABBRE TIATIONS
ADT
AE
AKT
ALT
AMPK
.4,SA
AST
ANC
AR
BLTN
CBC
Audroger depravaf ion tlrerapy
Adr.erse Er,eut
Protei* kilase B (Pi$) also knour as AKT
Alarure transarnilase
A\{P-actir,ated pr otein kfurase
Aspirin
Aspartale artrinolrausltrase
Absohrte neutrophil corurt
Androgeu rBceptor
Blood urea rutrogetr
Corrrplete blood cormt


Title: A Phnse 2 Randornized Disr'onriuunfion Trial il Patierrts u'ith Honnone-Depeldenr Ri;irrg Prostate-Specific
Antigen Progressiou Aher Locnl Thelapr, lbr Prostate Cancer Etalrrating the S;*uerg1' of l\,{ertonrin Plus Aspirut
{PRI\IA Trial}.
O"I
CINJ
CTTTJOO
CI
cox
C]T
CTCAE
CXR
dL
DNA
DSNlP
ECOG
CCRF
EGFR
FDA
GI
IGT-I
tRs
IRB
JAK
LKBI
S{APK
iv{g
nlL
N{RI
rUTOR
NCI
NF.KB
Ng
NIH
OR
OHRS
OHRP
PI.]K
PI
Pca
PSA
PSA DT
Rb
SAE
SGOT
SGPT
STAT
WBC
Conrpuler Tonrogaphy
Comnorr Tenrdnologry C'riteria for Adverse Events
Clrest x-ray
Deciliter
Deoxylitromrc leic acid
Data Sal'e6' hlomtoliug Plan
Ea stem C'oopera tir;e Oncology Group
Electlonic case reporl fomr
Epider"nral lrowth thctor receptor
Food and Drrrg Aclrnuristration
Gastoiutestiual
Irrsulin-like qrowth factor I
lnsul iu relreptor sub$lmtes
Lrstitutioual Rer.ierv Boar d
Janus kilase
Lirrel kiuare B I
\{itogeu-ac tir-ated protein kinases
\{illigrams
il{illiliters
Magnetic resollr[lce imaging
lv{aruualiau target of raparuycin
National Cancer Lrstitttle
Nuclear t'actor: kappa-light chain eilhaucelof actir,ated B cellr
Nauograms
Ofl'ice of Hruuan Researclr Serr-,ices
OlYrce of Hurnan Resealch Protectiorr
Phosphoinositide-.] -kirrase
Pliucipal Investigafor'
Prr:state C'ancer
Plortate specilic antigeu
Prostate specif--rc ailtigeil doubling time
Retinoblastorna proteirr
Seriorrs adverse everrl
Senuu glutanric oxaloacetic trarrsanrinase
Senurr I,lutauric ;:ynrr ic trausaurirrase
Signal transdrrcer and activator of transcription
\\,tite blood cell
'0rltldellce lrltell'a
C'-vclooxl'getase
.1


Title: A Phnse 2 Rnurlourizecl Disconriruratior Trial irr Patients t,itlr Honnone-Deperrdeuf Rising Prostate-Specific
.\itigen Progrressiol Atter Local Thelapl'lirr Plostate Caucer Etelrratrng the Slrrergrl'of \letfonuin Plrrs Aspirirt
tPRI\IA Trial).
nt,I
S1-)OPSIS:
-r>
ME?FORMIN
15OOMG'DAY
ASPIRIN 81MG/DAY
4 CYCLES
PO
{PSA rise>S0% from
baseline and minimum
of 2nglml rise in PSA)
n
PR
{PSA decline >25%
lrom baseline)
-)
OFF STUOY
METFORMIN 1sOOMG PER DAY
ASPIRIN SlMGIDAY
6 CYCLES
METFORMIN PLACEBO DAILY
ASPIRIN PLACEBO DAILY
6 CYCLES
CONTINUE
+,
Primary endpoint:
lncrease in 6 month rate of PSA and clinical progression in randomized patients from 40% in the
treatment arm to 80% in the placebo arm.
TOTAL NUMBER OF REGISTERED PATIENTS= 66 (assuming 10 patients progress prior to
randomization)
TOTAL NUMBER OF RANDOMIZED PATIENTS= 56
28 PATIENTS PER ARM
STATISTICAL ANALYSIS: With 28 patients randomized to treatment or placebo the study will have
80% power to detect an increase in the proportion of patients with progression at Gcycles from
40% to B0% with alpha =0.05
DEFINITION OF PSA PROGRESSION DURING RANDOMIZATION PERIQD:
lncrease in PSA by >50%above and absolute rise of >2nglml
CIN.' 4: r)S t 501
---)


Tirie: A pha-se 2 Randornized Discontirurarion Trial in Patier(s r.vith Homrorre-Depe[dent Rising Prostate-Spec'ific
.\rtigen progressiol ,{fter Local Therapy tbr Prosrate Cancer Et'alualirrg the Syrelg,r of Metfor:rifi Pltrs Asptrut
(PRA'I.\ Trial).
Or,I
1. Purpose/Specific Objectives
In this phase II pt'otocol we $pecifically pr:tlpose the follotl'ittg nius:
1.1 Prirnar.l- Endpoints
I .l " I To cleterrnirre t[e et-tect r:f uretfomrin aurl aspirin on the chartse in PSA proSlressiotl
irr lren rvith rising PSA nfler defiuitive therapy tbr localized prostate cancer artd
stal:le clisease cluring a nur-in period witli the stttdy regimerr.
1.2 Secontltrv Endpoints
1.2. I To deteruiine the" feasibility and sat'ety of atlruinisterirrg ruetlbnuitt and aspirirr
1.7.2 To detenrine the etl'ect of uretfomriu and a.spirin on PSA levels ancl the senun
obesit-v-related PC'a lrioumrkers (insulit. ICiF- 1. IL- l p, IL-6, anrl TNF-g)
2. Background anrl Significance
proslate .1"rr"", is the lrirst ctrrrurrqnlv diagno.sed catlcer itt tnales and the secortd leaclirrg catrse of
cleatS fi.6rn c&llcer i1 meu. Oue in every six luer is cliaErnosed with prosta{e cancer chu'ilg theil
litltirne. The Aurerican Caucer Society estirtates that chu'ing 3014 approxir[atel1" 233,000 lterv
cases of prostate cancer rvill be diaguosed ard o\rer 39,480 men r,vill die tlom the disease iil the U.S'
Trvelty t6 t'orfi percerlt of pafients undergoiug radical prostatectour,v il.2] and 30--50oir of palierrts
rurclergoilg racii"ti.',n tfierapr, u,ill esperience biocltendcal rectulertce rvit]rirt l0.vears [3],['l]
\\rhite there is no cu"r'eut stanclarcl of care therapy ilr patietts rvith PSA progressiott fcrllowing local
therapy w.ithgut detured rnetastasis. it is of particular tliilicultl' to utake treat$teut decisions in tliis
p.-,puiatiog of 1:atierrts. Despite a clearer tutderstanding of tlte usage of arrdrogett rlel:ravalion
it,.r.py (ADT)lu patientii *,ith metastatic clisease. there is no clefinitiie clinical trial or approach tcr
etetile whel alcl if to ilitiate ADT in this population with onlv PSA progt'essiotl alier local therapl'
[5]. Given the evenfinl progression to resistance to. arrcl tr:xicities r:t'. ADT. horvever. aclctitional
opiioor of less t6xic therapies r.vould be impacttnl to this large populatiou of palients [6. 7].
\.lpltiple rlechanisrnii ol'turuclr progression ancl drug resislartce a1s 1lo\\i tmderstood ancl prortide
potepiial therapeutic tal€rets. lrkrst nsirrg PSA only prostate cancel'patiertts aLe ltolrnc'rttal sensitive
alcl clepencl liairrlv ou the classical auctt',.rgett receptor-sl6lualirrg palltivav. Tltrs classical pathrvav
stafis \;ith a1 a1c1.sgeu trintlurg to the ancbogen receptor (AR). the complex then transporls fu'otu
the cltosol irrto the cell nncleus ald bincls to a specitic $equerce of DNA attd irlterar-:t rvith other
prpteins. resglting in up- ol clcrrvu-reqrilation of specitir gere tralscriptiou [8]. Altemative atttlrogeu
recepror-siglalilg parSw,ays. such as Pi3K/AktlurTCIR [9-l l]. N'{APK [12-14]. Wut{reta-catenirt
1r:1..rffiiTAT If6]. harle treen iniplicatecl in prostate carcinogeuesis. A mrtutrel of clinical tr"ials
i"rtirg illibitors"talgeting ttre alteilative androgen receptcll'signaling pfltltrvaYs. such as Akt.
EGrR in6iSitt-rrs. irr treatius risiug PSA ouly prostate caucer have treett perfonuetl clr are crtuTentl)'
orgoirtg.
Iletformin activitv in c:rncer: I\{ettirmrin is the urost r.viclel-v useti antitliabetic tinrg because of its
eet.fects'IrrterestirrglY"recerrtshrclieslraverepcrt.tedtlratmetf0ru}i[
can block t5e grorvt[ of riittereur tumor t1'pes [17. lSl. \,{etfor:rrin cattses secoudatv inlribition of
Protocol \.'
6


Title: A phase 2 Raldonrized Discontirnratiorr Trial iri Pnrients rvith Hotlrtone-Depertdertr furing Prostnte'Specific
L,rrig"r, progressiol .{fier Local Thelap-v for Prostate Cancer E'l'aluating the S3'rrerg,v of lr'{ettblluirr Plrrs Aspirlt
tPRII'IA Trial).
i,,'I
the rlTOR coruplex yia actiystilg Alr.,1P-activatecl protein kiuase (ANIPK) [19]. Insulirr ald Lrstilin-
like grorvrh factor I (lcf-l) nre kev fnctors in prornoting crucet dev'elopnent. Birrclittg of
insulinilGF-I to therr l.eceptors results iu receptor autophosphorylatiorr attd actlvatiou of receptor
t_vrosine kiuase. frrllou,ed i1'qrosine phosphorylatiou of ilsulin receptor srtbstrates- rvhich fiuther
prt",pagates the dorvnstr*urri pi:XTAKT:'miOR sigualirrg patlrr,vay [20]. lr'Ietlbmriu is obsetved fo
i*d,r.. h-vperglycernin. iurprr:rre glucose utilizatiori. artd recluce h'ee fatn' acid utilization and
glu",--,nec,genesis. Subsequeiitll,'. metf,:nuin recluce-ii insnlin nnd IGF-l production. Ir'fetfounin uraY
.tohrt, rirTOR activatioo tlu.ough AlrIPK-indeperclelt patlrivay - inliibitri:n r:f iusulinjlGF-I
sigualing.
N{etfomrin has also been shorvn ti: inhibit c-vcliu Dl expressir:n ancl retirtotriastomn plotein (Rtr)
phospSorylati6n. rvhich results in the inhitlitiorr erf cell prolit'eration [21]. N'{etfonttirt inhibits
orarogurr-ilchrce6 ICiF-IR up-r'egulation in prostate cancer cells tr-v disnrptirtg ureurbratle-iritiated
a14roge1 siglaling [1i]. These inclicate ruetfonuin rnight have direct rnhibitor-v eftbct on prostate
cilnct-"r cells.
Aspirin activifi, in cnncer: Aspirin (ASA) is a salicl.'late dnlg. otten ttsed as att analgesic. }
@lal0lvtuedicatiott'ASAalsoltasbeerrrvidel,vttseda-sattattttpIateIetttl
the lrr.everrtion of carclio-cerebrovascular diseases. ASA is ttou-selective and irreversil:l.v ur]ribits
both COXI and C:OX2. ASA clearlv detrorrstratecl its lole iu preverttitg !:Ancel'clealh as described
in a ureta-anal.vsis of eight ranclourized clinical trials - the largest dlop in risk rvas {br cr:lorectal
caucer iruti sorue ,n,,-,re m.rclest risk ret{ucfiorrs for several other cr:trur}on caucers. incltrdirrg lutlg a[cl
prostate [23]. The lrechanisms for its chemopreventative effects are, horvever- rtot clear ,vet.
Various li-v-potheses [ave been proposed: ttte most accepted ar]]ol]g tltese proposes tltat rts ar(i-
callcer actirxr is lrec{iatecl tlu's11s5 Cl(:X-: iuhibitir:u [3'{^ ]5]. Other possible rrtechartisrtts inclttclc"s
inlibitiol of NF-kB [26]. irrductiou of pol,varnine catabolisur [27]. nrtribittou ol mTOR signaling
[2s] aucl activation of atttpx [39]. etfeos ou PI3K pnrhwa!' [30] or its crosstalk wrth (:Ox-l. antl
iuclirctiou of apqptosis tluolg.ti citirer pathrva),s. We receutl-v* tlemonstratetl that C'OXibeta-catenitt
sigualing patlrrva_r. is activatecl iu heruatopoietic stern cell self-r'erterval attcl letrkenmgenesis [31].
aba liigill exerl its direcr imti-proslflte cancer eltbcts tlrrough inhibiti,:ls of C'OXI. nrloR.
AN{PK. \\rnt,'beta-cateuin auci PI3K pathrva,vs aud uright lre s1'nergistic rvhen combirted rvrth
uretfonuin.
\,Ietformin. aspirin and PCI:r tumorisenesis: A recent nou-lattclortlized shrdv shorved tltat
rnettbnuiu use was ,.r"*^**t".l ,.'fi u :g0", r=,t*tion in PCa urortalit--v tor every atltlitronal 6-tttotttlts
of post PCa diagnosis exposrue (oclds ratio [OR] 0.?6; 959'o cortticlence ittterval [C'I]. 0,64-0'79)
corirpared rvit5 other auticliai:etic dnrg use amorg diatretics [32]. C'orrsistenl with this hnding-
uretiomdn rxe is also associated wiih a re<lucecl risk of distant tnetastasis. clevelopuetrt of
castlarion-resislant pCa (OR:0.07. 95oo CI 0.008-0"55) folloiving biochemical rectuTettce. attd
sverall rlorlality fiurollg llrcu receiviug extemal beatn radiatiorr [33] A randoruized trial
deuronstrateti that nrettbmiu use (500rrr[ tluee tirues a da1' ti:r,11 days) bet-crre stlrgerv reduced
ca,cer proliferatiorr rlte b1. 33o.o in the surgical speciueu courpared rvith pre-surgical btt'rps!'
speci,uen [i.l]. ln ncldition. ii receut phase 2 tiial rn patients rvith castration-resistant PC'a shr:rved
ruetfolniu treatruent firr ?-l rveeks rnay indut:e disease statrilizatiou attcl prolong the prostfite-


Title: A phase I Ra[tiorrizecl Discolriuuariol Trial in Patierrt.s \,\'irh Honnone-Depertderrr fusing Prostate-slrecific
A$tigen progression Atrer Local Tirer.apy for prosrate cailcer Elahutirrg rlre syrrergl' of ltlettomrin Phrs Asprrul
tPRI\.L{. Trial).
it,I
specilic autigen (pSA) doubliug rime [35]. Frrtherruore. nrettbnniu sigrriticailtly irrliibitetl the
t,nro, grorvt6 i1 LNC'ap *.,rogrift urlce i:oj and reduced PIN clei,eloplnellt ilrtcl P('a lesiorts ur Hi-
11,I.vc ruce [37]. For aspilin. ilr"r.,, s,:irre-evitience t'or a protectlre ettect agai[st PCa [38-40].
horvever. coltroyersy rlata suggesting no associatior ltrs been tepotted [-ll]. In a longittrclirlal
coSorl study rif -5955 patients wiih locilizecl PCla who rvere tbllowecl l'ol up to l0 yt-'als. c'hoe el nl"
r.eceltly repgrtecl thai aspirin use wfls iudepenclentl-v assr:ciatecl rvith a lorver risk r:f P('a-specitic
,rroralitl,(adiusteA hazarlcl ratio. 0.43: 95o.i CI0.ll-0.8?) [42]. A s-vstentatic rueta-arralysis shor'ved-
tlat aspiriri rrse clecreasecl the toral risk of PC'a by l7o,'o i959o ('I 0.77-0.89) arld clecreased the rtsk of
at{vanced pca b-v Igo.o (g500cI 0.7:-0.92) [.13.,1.{]. These results suggest thst metformin lrnd
aspir"in coultl be ttsetl in prevenfive nnd/or ther*peutic strategies for PCa'
rnd
tiF-
ST
\vill': NF,rB. a tuecliatr"rr of
rtflarrrrriato,-,,*,po,irrogerresisarrdisilowerueIqirrgasaliirk
befu,een iu{iauurratit''u aucl cal}cer. Aburrrlaut tlata stq:pc'rrts a key role tbr tlte iriF,r''B signnling
paltrrvay in c1r1t;ollirrg the irriliation aucl progresiiiott of htttttan callcer. l-tre NFrB patltway i5 3p
irnportant contributorl to pca ruetastasis [45-+7] ald actir.ation of NF,IB sigrralirtg proruotes
.oitrot*-r"*isralt gron,th rrf PCa [{8. 49]. STAT3 rnediates a coruplex spectl'Lun of cellular
respolses iucluclilg intlarrunarion. cell proliferatiorr and apoptosis. Constitutil'el-v flctivated STATI
lai been in1:licatetl iu a uugrbel ol cancers. inchrcling PC'a [50-51]. l{tl'e itt4ror1an(' inhil:itiou of
SI'AIj las been 5[16rvg rg iuduce apoptoxis in PC'a ceils i5l-53]. suggestiug SfAI'3 rrtay tre an
excellent niolecllar tnrget ibl PCa pievention autl treatrnent. Aspirin has beett extensivel!'shrdied
as a 6OX illilrirr:r (Figure l). It has also treen shou,tt to inhibit NFxB activation [-s4' 55]' atlcl to
incluce npoprosis tlu'otri| rlorvn-regulatiou of uterletrkin {fL)-6-STAT3 signaliug patllva;*s [56.
5?]. Theie 6ata inclicare tlat NFTB,STAT3 pla1, a critical role in the pleveulion of aspiliu against
pda. tr{etl61ui1 lns alro treeu sh6w.n ro inhibit STATS phosphorllation attd ilorvttstreartr sigrtalilq
iu triple-negatrve breast cancer cells 158]. ancl increase the seusitivin' of resistant cells to crsplatin
br- suppresilrg STAT3 activitv rvitlir:ui activation of All{PKr;,. suggesting STAT-I is a critical
l'egtililtor of trtetfourtiu action [.i9]'
lletformin. aspirin antl AltPIrJmf'OR siennling pathlvql:: :*-Ieltbnrriu tray'diruiuish the etl'ects
ofinsulirro,,n,,,,.',,@orrghilrlribitiorroflrepaticglrtcc'tteogetresistlr
iucr.ease irrsulirr serrsitrvi[,. tlnrs leading to reclucetl circulating insulirt aucl IGF-l letels (Figure l)
[60.61]. Bilctigg of iusirlin,IGF-l to their receptors resttlts itt receptor autopltospltotYlatiou and
actir,arion of receyrtor tl.rosine kinase. follorvecl b-".- tvrosiue phosphorl'latiorr ol insulin Leceplor
s*bstrates (IRS t-lt. ivhich fruther propagates the clolvnsrreaur phosphaticl;-linositol-i-kinase
(pI3K)iAKTirlTOR siglalirrg parhu,a1, [20]. Ir{ettbmrin may abolistr urTOR itctivation tlu'ough
i,hibitiol of ilsulirr,ICi-t srgriaturg an Alv{PK-inclepeudent ureclianistu. or tluough liveL kirta.se
Bl (LKBI)-rpe4iated actiyation of A-lr.IPK an Ah,IPK-deperrdert urechanisru [62]" \\tile AI\"{PK-
4epentierrt suppressi*n of ruToR signaling remains the ke1," carrilidate utechanisur of altitttrttor
actir:u of lrettbguin. .rf pflrticglil uote is that mettbnnin rua,v also tars,et ttre irrtlarrullilttlr)'
corlpolrerlt. leadiug to tuuior recluction [63. 6a]. Salicl'late. as a tnain utelatrolite of aspiriu. i$as
rece,tl,v repol"ted rg clu.ectlr, acrivate A|UPK ,"iir*it-v [65]. Dirr eI dl. recer]tl}' shorvecl that aspirirt
aloue or courbiuatiou of aipiriu anrl rnetfonrrin ac:tivites A\,{PK and inhibits niToR sigrralirlg in
Pro


Title: A phase I Rauclonrized Disconrirruation Trial il Patieuts u'ith Honuone-Dependerrt Ririlrg Prostate-specific
A.,rige, progressio' Aher Local Therap.v for Prostate c'ancer Etalrratirrg the s,l'terg,l of N'lettbfl,il Plrrs Aspirur
|PRII'IA Trial).
i,t'I
colorectal cancer cells [66]. Potential il]echauiuus CIf synergistic actiorr of these trvo agettts in
paucreatic cancer have treen re\''ie$ed con$l'ehensively [67]'
ln r.iro me(ltauiim studies: Recent tvork in the laboratotY of Dr' Tati and Rutgers (]IN'I
ffiattt:rtolttteltbtrtrittarrt{nspirirtatlorvcr..rttcenlratioltslta<lsigniticarrt
synergistrc etlbcts on the urhitritiorr of cell riabilit-v aud colo[v foflIation (Figu'e -1)' aild resulted in
a sig*ifica*t clecrease in rtre phosphorllatiou c,f mToR ancl srAT3 {Figu|e 4) i[tlvo PC'a cell lirles
LnC'ap and Dul'15.
Fig. l. lletforruin aud :rspiriu sllergisricallf inhibit cell r"iahilitr nud colonl' formntiol iu both LuCap
aud Dul4S cells. A "r,a ri, l1Tt nrr[' tix rlie cell tiabiliqv of LnCrp nnd Dul45. respectivell'' Cells t'ere
h.eaterl rvith urdiciriecl colcenrlaticos oirnetlbmrur and arpirui. slotte or in rrrmbittation for ll h: C' C'lonogerlic
assay for LnCag: rrnel Drrl45. ('clls NcIc rrcared {"ith urettbr:uifl (i 1r&{'} arrd aspirirr ii rn\'{)^ aloile or-ir
cornbilatiorr 1'or 7: h: then 1000 treated ol rurtreated cells per u'ell u'ere seeded in 6-rvell plates and clrltuetl lbl
rnotler l0 da,,--s: D. erraltilicarrpu of c,rl,:n-v- tbnnntiol tssay in LnCap ancl Dul'lS cclls. rtrpcctivelv' l'let'
lr{crlbnniu: Aip. Arpirirr: eP' 0.05. c.rrttptrcd totltt corllrol. v+p'::0.05 forthc tcst oisyretgr''
6i'
t !.
E .,,
E ,,,
(J'
Fig.l. ltrtfor.rniu nnd aspir.irr sr^ner.gisticallv inhibit thr pbosphor]'lntion -of urTOR aud STAT3 in
both LnCap (A) nud Du1{5 td) cel"is. (ells \iete tr"entid rrith.s Iul{ tncll-r:r:rrirt" I m}{ a:lririrt or a
conrl.:i'atiou tbr l-t. 'lS. o, ;; .1r.'r* .,1r*"tivel1'. Plotcilr ex;rles'ion lcr"eli *i rrff0R'lP-rrlL01-S]j\ f i.nrrtl p
STAT-I rvere dclcuuiner-l try \\:e>tcrrr t',lor. The Iatior ol p-TiTORI).TOR and pTSTAT-] STAT-i rve
calculatetl antl rrr.tuualize.l trr lhc ctrlttrol. Cont' (t-lntrol: lv{ct' }r{etfonlin: Alp' Aspir'in: Com
c
6()
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Title: A phase 3 Rantlourized Discontinuarion Tlial iI} Patients rvith Houttone-Depelldent Ri*ing Prostate-Sp*ific
,turtige, progressio' Aher Local Tirer.ap-l- tbr Prosrnte Cancer Etaluating the Syrelgy of lr'lettbnuin Plrrs Aspirur
(PRI\I.{, Triali.
nt'I
Clinicll trid:
Basecl on courpellilg epideuriological and preclinical iiata sugge$tins that trletfomrin a[d aspirin
,r.oy u., syrrergisticaily to inhibit prostate cell grorvth. we r.vill cotrchtct a placebo-contrQllecl Phase
II inten entiou sfu<h,. using a ran<lornizecl ctiscorrtinuation desig.n. The prima$ obiective is to
cletenril,e if ,retlir,,il pl.r*'aspir.iu prolcrugs the PSA doublirrg time corrtpal'ecl-to trse of rrtelforruitt
alone i, p.tie*ts rvho [ra.,,e statrle psA irahis cluling a -1 montlt nut il period of treatrnettt r'vith br:tlt
agents.
i, tSis study n rirucloruizerl cliscoulimmtion design rvill be txed itt orcler to address sotue of the
rurique cr",rsicleratic,us in testiug a regiruen that woultl lre considered effective ii it leads lo clisease
statrilizatiou aucl that clepends .ir, r,ro.irrlatiou of a bloocl based bilurarker as the prirrrary detenniilant
of ethcacy.
As noted by Ratia* et.al. ..a raudourizeil discoutinuatiol clesigur irritiall.v lreats all patieDts rvitlr the
study agerrt (stage l) arxl lheu rauck:urizes in a clouble-trliud fashion to cotttitttting therapv or
placebo o,l,v thoie patieuts rvhose tlisease is stable (stage 2). This clesign rrllorvs the ilvesti-qfltors tcr
detenuine if appareut slorv tuuror grclwlh is attritrutatrle tr:r the tlrlrg or tn selectiott of patierrts rvith
*ahually *161,,,-gr,:wiug nunors. Iiy selecting a rtrore ltourogeueotrs populatiol. tlte rirudcittized
portion of r5e shrdy requires fervei patieutr thatr rvould a study raudoutizirtg all patients fit eutry''
the cl..ig1 also avii6s pr:tential c.ruiburcling becatue i:f helerogelteolls tutnor grr:w{h' Becatme the
two raujc,ilrl-v assigilecl treatrrettt gr'oups each courprise patierlts rvith apparerrtly slow grorving
turuors. ouy jitt.r.uce betrveen the groups iu disease progressiou atier raudotttizatiott is more likely
a res*lt c,fi5e sftrcl1.tlnrg aucl less lkel1, a result of iurbalauce rvittt respect to nruor gtorvth rates".
Utilization r-rf t6is ctesiln alkrrved irri,estigators to tlelelmine that sorat-eilib catned stafrsticalll'
,rearri,glll disease stabiiization thar rvas sulsequeutl.v conlinned irt a pltase III trial leading to dnrg
approval.
hr patierrts ivith rising PSA- rhtgs causiug disease stabilizatirirt woulcl be expected to lead to a
sloivilg is the rate oli rise in tlre PSA. ivhich can also be explessed as a lerrgthening of the PSA
doubli,g tilre. Ivllltiple priix phase II tr^ials tbr rneu rvith lisiug PSA^ inclurlirtg several ratdontized
plncebc,'c,:ltrollecl trials. have Rssessed changes h PSA doubliug time as art endpr:irtt. Iu these trials
it ,*,n* uotecl that patients in the placebo amr often have au increase irr the PSADT atler going on
stldy'. As notecl by ealler et al.. irr a Rosiglitazone trial irtvolvurg 106 patierrts. 73qo of patiertts on
placet o had an iir.-rease of PSADT in excess of i00q,a. arrd 319'b exceecled 2009'o in PSADT
ielgt5euilg. In an Arlaseutan trial involviug 222 patiertts. 78o'b o{ the patienls on placet:o had a
le,gtlieni,! of pSADT. Iu a celecoxib trial involviug 78 patieuts. 20oo of the patieuts ort placebo
had .r?00o.0 irrcrease of PSADT. ln these snrclies. lhe incrcase irt pre atlcl on-treattttertt PSA
d.*tiligg tirne has beel attributeri to clifference tretrveeu spacing iutetr.al and ntunber r:rf PSA valrte;
collectecl i1 au rurcoptr:olleri "pre-snrcl--v period cottrparecl to the legrtlm irtletvals al lvhich PSA
valtres trre collectecl once r-xt sht<lr"'.
11 the currerlt clesigl all sutr-jects tvill receive shrdy therapy tbr :l c-v-cles. Druing this peliod PSA
rvill lie rneasruerl at rnontbly iuteryals in order to dereflnire a PSA cloutrlirrg tirne itt a urtifonD
maluler. and to otrtaiu a r:elatir,el,v lronrogeneotrs population of palieuts for randotnizatiotr' Patients
Prorocol Versiort 8.0 IJl0lr?011
Pr"otocol Versiol 8.0
l0


Title: A phase I Raurlorrrizeri Discofltimrafior Trial in Patieutr r'vith Hornone-Depertdent Rising Prostnte'Specific
fuitigen progressirrrr Alrer Locnl Tlrerapy tbr Prostate Cancer Evalrrating the SFlergl' of Metfoflrrirt Plrrs Aspirui
fi]eeti,1g the strdy specitied cletiuitiorr of statrle clisease r,vill theu ploceed to raudomizatir:u while
pntielti neeturg criieria ftrr PSA progression will come off stutll" aud those patients lvillt PSA
i.rpou." ivilt coirtioue o1 rherapi, rurtillhe shrd,v defiuition of clisense pro$iression is uret-
Atier lhe rr,r i, pSase patiellts rueeting the criteria for sratrle rlisease'will be randotnized to cotrlirttte
therapl, rvith lrettbprriir ancl aspirur or to placebo utetfbnuilt. ancl placebo aspirin'
The secorrclary,qtrjectrle pf rhis shrd1, i5 to cletemune rvhether tlte interreutiott umy rnodifi the PSA
le'els a,t{ tire serl}nl obesiq,'-r'elaied PCa biomadiers. Tlre tolerabilitl of ailct cotupliance of
ntetlortnilt att<l aspilirt tl'ealuleul in tltese strtrjec'ts rvill also be evaltmted'
3. Participatinglnstitutions
treated at the
par.ticipale in
rvell.
I\'feurbers of tlre CINJOG ttehvot'k tlta-v also
patrents nraY
Gd arrd treafecl al tltese rerpeclive irtsttttrltotn as
"1. Experimentll Design and \'Iethotls
Eligibll patienrs ivith rising PSA after clefinitive tlterapl' of localized prostate carlcel'- uo vtsil:le
,retastatic t{isease or, .ortJrr,ional irnaging snrdies including CT scart of the abdomett and pelvis
ad br:rre scas. aud a pS;\ d*utrling rinre of gleater thau 6 cy''cles ivill be lreatetl rvith 4 cyr:les of
metlbnniu 500rugrl000urg BiD and aspilin Ilrng:day.
{.1 Disease Assessment After Run In Stage:
After 4 cycles of treatrueut patients with disease progressiorr (PSA increase of :"50o"b and
ruiniruruu qf 2lg,rrrl rise rn f.s;L; rvill corue off study. Patieuts rvith clisease lespouse (:'l-5o.';
declile in PSA) rvill cotllintte ott sfttcl,v agellts.
patients rvith stiible clisease (rrot ureetiug criteria fcrr progressiol or stable disease) r'vill be
ralclornizecl to contiule on the sftrcly r:egimen ol teceive placebo therapy for 6 c-vcles"
4.2 Run In Strge Treatment:
N{etfcuruin treatmeut rvill be started at 500 rng frvice daill'.
is uotecl atier 2 rveeks it rvill lre increased to 500 urg rvith
is the talget dose tirr lhe terttainder of the shrd-v' Aspir-in
lbod.
if to GI toxicity'' gracle greater than I
breakfast,'1000 utg at lredtiure^ n'hic]r
8l rrrg rvill be takett ottce daill'' lvith
{.3 Randomizltion Stage Trentment:
patielts ureetiug criterl for randourization ivill [:e randourize<t to contiuue therap;- with
ruettbmrig 500 ilg in the momiug ancl 1000 rng at nig.lrt ald aspirin 8l rng per dav ancl err to
placetro ntet tot:rf tt arrcl. placebti aspirin.
Rarctgruizatiou rvrll tre pertbrruecl baseil ciu a rancl:ruizatiou schedule generated b-v statistician
(Dr. Lil) psilg a stratiliect ranclomizatiou method in order that the nurubers of obese patients
(BN.{I j 30) ou eaclt g,roup are tralauced.
ll
Prorocol Ver':iol S.l-i ll r:11,:tllL
I


Title: A phase ? Rnutloluizecl Discoltiuuariol Trial irr Patierrts witlr Honrrone-Depeudent Risirtg Prostate'specitic
A'tige, progressiorr Alrer Local Tlrerapl,for Prostate ('aucer Evatrrating the syrergy of N{etfonilin Plrrs Arpirut
tPRI\{A Trialt
PI:
4.{ PSA ResPontler Treatment:
Patietts uleetillg criteria f'crr PSA resporse ("35oi' decline in PSA duriug the nut-ilt phase)
ra,dourizalir:1 rvill be assigrred to contirnre therapy with rnetfonnin 500 rrrg in the monting aud
1000 urg at night. antl aspilin 8l rng per tlay mltil disease pt'ogressiott'
4.5 Disease Progression Criteria During Rnndonrizltion Stage Tre:rtment
Disease progress]on druing the ranclomization is tlefurecl as l'ise in PSA try >50o,tr above baseline
and absolut.l ir,.r.u*. of 2ng,rnl- or radiographic progression
4.6 Duration of Follorv-uP
For tlis protocql. all patierits, iuclutlurg tlurse wlu: cliscoutinue protocol therapy earl.v' rvill be
t'ollorvecl tbr re.sponse'(or progression) aud for sunival for I year {rorn the date of registration'
All patieqts ruuxi also be folloived tluough compleliott r:f all protocol therapy-
5. Patient Selection Criteril
5. I Inclusion ('riterin
A patiell is eligible ltx errollnteut if alt of the frrllorving irtcltniort criteria are tnet:
5.1.1 palieilts rvirh histologically proveil prost0te cancer h'eated rvith surgery. racliation. or
the corlbilatiop of ilrgerl-ancl radiation ol'proslate caucer (lrretastatic to regional
lyrnph loctes) rvith resiction of the nocles. ',vho now has a risiug PSA vahre after
rlefinitn,e local therap.v, and uo visitrle urctaslatic disease on conrreutioDal ir[aging
studies
5.1.2 patieuts mrst hlve undergone local treatrnent via prostatectolllY or radiation therapy.
5.1.1 Patients nurst have PSA progression atiel local tt'eaturent:
a. pSA I'alues fbr parienti nft"r rlug.ry (or surgery antl salr,'ageladjuvattt radiatioil)
lrust be greafel' than or equal tc 0.2 rtg'rrrl.. deteuuilrerl by frvo measlrrelne[ts- af
leasl I ruollh apart and at least 6 urontlts atler prostatectorny
OR
b. pSA valtes for patieuts after radiation must be greater thatt or equal to 2.0 nglurl
greater than the riaclir achieved aller radiatiou. detenuiuecl [r-v trvo [leastuelrents at I
rutouth apart aucl at least 6 mouths after the radiation trcailuent is cornpleted.
(patients rv[o received adjuvant or salvage radiation alier prostalectouty ttusl have
PSA of gl'enter thatt r:r etlral to 0.2)
c. The t'rrst tr.vo PSA valrtes (in 5.1.3a or 5.1.3b)'
uxnt r,rll be rising (i.e., there ilt$t be au overall
l,alue citntlot be Lrrver tharr the firsl value).
d. PSA dr:ublirtg tirrre usiug the rrrliscc.olg PSA
greater than.4 fironths
5.1.4 Baselile bone scau. chest x-ray ancl CIT/N{RI of abdotnenpelvis demonstrating no
uretastatic disease.
along rvitlt n thircl (pre-study) r'alue
rising trajectr:r1'. such tltat the third
ctotrbling tirne calculalot' musl be
l2
Protoc


Trtle; A phase 2 Rarrr[rurizetl Disconriuuarioti Trinl in Patierrts $'ith Honnone-Depertc{enf Riring Prostate'Sper'ific
,&itigen Progressiou Aher Locnl Tlie|ap1' l'or' Prostate cancer Elahraling tlie Slarergl of ir{ettorlun Pltrs Aspirui
{PRI\lA Trialt
Or'I
5. l.5 A bone scalr arrcl a CT or lv{RI abriornsllipelvis and chest x-ray.(CiXRl or chest CT tcan' rvill
l*o. ioo, pert'o-plediviilul t: weBks ol meantetrt stafi, Rildio$aphic as$e:slrellts will be
selecred b_r:dre amelding physiciail as clilically urdicared.
1.6 Ase ." 18 years
1.7 Eslimatecl life expectallLry of at leasl 6 tnotrths'
1.8 ECOG pertbtutartce status.:2. (see Apperrdix A)
l.g A \[iBC::,3500,,[11_ ANc:*1500./pl. heuroglobin:, l0 gldl. and platelet count
> I 00-000irl are reqtrirecl.
5.1.10 Adeqtrate r.elal flnction r,vith estirnated GFR tr.v Cockcrofl Gault of greater than 40
Ir'1I. pel utitttlle
5.l.ll Total bilimbin trust be lvithiu l.5x the uorural institutir:rral liurits. Iitotal bilinrtrin
is outsicle the nr:rural institutiorral liruits. assess t{irect bilinrlrin. The direct bilinrbin
glmt be rvitSiu uornal pararueters. Transatrrinases (SGOT art#or SGPT) rntxt be
5
less than l.5X the ilstitutialal upper limit of norlral'
l.12 Patierrtsi ullrst ltat,c. a $enun tofat testoslerole level .,:150 lgldt' at the tilre of
eu^olltuent rvithirr l2 rveeks prior to tattdourization'
1.13 Patierrts urust sigu irtlbnued couserrt.
5.2 Exclusion Criterirt
A patielt rvill not be eligible for this strdy if arry of the following exclusiott criteria al'e met:
5.?.1 Serir:,us .,,rnionitant sl.sternic disoider that rvotrlcl coruprornise the safet-v of the
patierlt or colllprotlrise ihe patiert's abiliry to coruplete the snrrll'. at llte discretion of
.\
5
5
tlte investtgator.
5.1.1 Patiertts mav have received prior ADT irl
setlittg^ btrl uttrst t:e otf therapy fr:r at least
-5.2.3
-5.2.l-j
the ueoailjrtr,attl. acllttvant auct''or salvage
3 urortths arttl ltave a tr'slosteror,,a lq1'el :'
5.?..1
5.?.5
5 3.6
5.?.7
5.3.8
s.2.9
5.2.10
5.3 1I
5.2.12
150 ug,'dl.
Secoud primary tttaliguartc-V except tnost siht carciltoura (e.g adequatelv tt'eatecl tou-
,uelau..utat..,us'carciriouro of tlr" ikirrl ot orlter tualiguarlcy colllpletely resectecl rvith
llo recullence.
Patients ivith l-vpe ll cliabetes cruleullv ltlt'earlv ort rttetfotrrrirt.
patielts takptg aspirin for prer,iousl,v cliaguosed carcliovascular clisease.
Patlents rvlto tieceiveit aspuiri or mettbnnin r,vithrn the past 38 days'
patielts takilg uredicatious r.vith krowrt interactiotrs r,vith tuetfonniu or aspirin'
Patients takiug rvarfarin or platelet inhibitor*'
Patie'uts requiling cluotric txe of NSAIDS'
Other cotlctureut experiruental or ittvestigatir:nal rlntgs'
Prior history of lactic acidosis or uretatrolic aciclosis'
Patieuts r"itl, t i*tory of GI bleetiilg aucl peptic ulcer disease wit[il the past 6
urrrrtths.
A1-y nrstable. serious co-exrsliug rueclical c,r:nclitions including bul uot linritecl tcr
rulncarc{ial iniarction. c6l'onflry b-rpass surgeryr. mtstable angina' cat'diac
an{r1,tlunias. clilicalt-v errident "oog*riir* 
hearr tailure. or cerebt'ovascttlar accidertt
rvithitr 6 tttottths prior tr: screening.
l3


Title: A phase 2 Ranrlorrrizer1 Discontiuuation Trial in Patier(.s $,irh Horruone-Deperldertt Risirtg Prostate-specific
A'rige* progressio, After Locnl Thelap-v tbr Prosrate C'ancer Etatrratirlg tlre Syre|g-l of Mettonni0 Pltrs Aspirtrt
tPRilvA Triall.
i,,'I
5.3 \Somen antl \linorities
il,{e1 li"oru all raciaUetluric groups ale eligible lbr this stucly if tlieY meet tlie eligitrility criteria'
Wonen rvill not be eligible tbr this shrdy as prostate callcel'does ttot occtu iu wclulell
5..1Chiltlren
Onll,.patie6ts l8 years of age or older rvill lre eru'olled on this shrcll. since prostate cancer does
ruot occrtr in childleu.
5.5 Stud-v Enrollment Procedures
;\ copv of tlre iustitrfiorr's I
,.erl igtbllr:cl cousenl clocuruettl art<l rvritlen justilicatiog
esearcli Services (OHRS )
irn-v partic rpetlllg lnstlttltloll ula-\
ffiDSpIoPoSe(ltbruseatapar1icrpatirrgirrstinttitrrrtrttntberer.terved
a,cl approvecl trr. the C)HRS Regrriatorr, Atlairs lr,Ianager ancl all cloctuttenfs nlttst lre received
(i.".. ing apprcx'ed clercurrrentaiirur. IRB approved cortseul fomt. See Secliott l5.l ferr a
courplete Iist of resulRtoll iteurs)
Participatingi,,@isterpatietttstlrrotrg1t,n"IRegistr.attott
f)esk telel:horte
. patielt .lenr..,grapiuc irf@ 
ciated snrclv-
+..i1.--i,g,rrir|iffiFlliiiilcon4:L'rerl signntuie page r:l the consc'nt lirnti and additioual
sorure clqcunrepts if requested by OHRS ntust be seut to the registl'atiorr desk. Ortce tlte OHRS
Registratiol Desk verides eligibili\.,. a ruriqrre patieut stud,v nuurber rvill tre isstted. The patient
rvill not lre icleltitiecl try narne. This is the point that the patient is considerecl on strrd.v-.
Patients must gg,[ start protocol treatment prior to registrttion.
If a patieut tloes rrol receive all)' protoccll ttrerapy. ltaseline rlata r,vill be collected and sutrmifted
orr tite pre-sntrl,v alcl tbllorv-up elecmoric case l'epofi tbnus (eCRF) tluough Chrcore'S" The
reasol 1:r uot staditrg protocoi therapy rvill be doctunetted in the "follow-trp eCRF"' Case
repor1 fonn conrpletion instnrction.s and traiuing rvrll [:e provided to each participatirg
irrstinrtiou 1:rior to stttci-v activaliou al ltre participating inslitution'
6. Studr Paranreters
The lbllorvillq tesfs ant{ evaluatious rvill be pertbmtecl accorclirrg to the schedule belorv.
no..tlrr* 1i.e.ipre-snrdl')evaltrations rnust lre pertblureclrvitLin { rveeks (*'- 3 clavs) after:
eru.olhueut. ilrrd 1x'ior rl therapl'. tmless otherrvise inclicatecl in one of the to1tlyt1s Usloivlitl the
talrle. Tite snrcly cltrtes. coll'elatlve sntdie
to the sutrject's ittstuartce coillpatiY'
ll


Title: A phase 2 Riurr{olrrized Disc-onti$rafiorr Trial ir} Patients wirh Honnone-Depertdertt Risirlg Prostate-Specific
A-rrtigen progressiorr Atrer Lr:cal Therap-v fbr Prostate Cancer Er:alrrating ihe S-l:relg.v of lvletfo[nin Plus Aspirut
Er,aluatiotts
Pre-Shtdy
Ott
Treatrnent
(er.ery.l
weekri + j
days)
Randomization
Da1' 1 of 1"
Ciycle
Post 4 N,'Ionth
Lead-In
off
Treaturerrt
(+30 days)
Follorv
Up'
hritial Historv & Phvsicalr
x
Interiut Histott, & Phvsrcal
xr0
X
Toxit:itr Assessmertt
x
yg
x
ECOG Pertbnruttcc' Slattls
X
xr0
x
Weiebt aud Vitals
x
x
x
C'BC'. drttelential. platelets
xl
x10
N
Senuu Cheruistriesr
X
xl0
.\
Lir.er ErtzYmesl
x
\
Ratlioqraphic Assesstnertts{
x
('orrelntive Snrclies:
X
X
\
C'orurrliattce Assessttrettt
x
x
Salicvlate levels6
x
\6
Proslale-specific anti gen
(PSA) *
\l
x
\.8
\
.\
l.
irreillr.ithirratr.eek,rfrtarrirrgClDl{thisPSA
*'ill ertablish a baselile to asses$ retpogte and rrill ttot detenlrire eligibility)'
hrclucles : E lectr olltes. Calciurrr. BtiN. Creatirrirte. Glrtcose'
I,cllrjes: Total arlrj Di1ect Bililrbil. ASTi.{LT" Alkaline Pirosphatase. Albrtrnin- Total Prntein'
"\ botte rcatt artcl a C-f or N"IRI ab<logrerl,rpellis arlcl chest x-ray ICXR] or cherl (lT rcan' rvill liate beert
perlbnpe6 ,,rit1i1 1l q,eeks of lreaturent $tar1. Radiopraphic $$ses$Irlents will be seletted b1'the
-1
4
attenclirtg physicinn as cliticall;.- irtdicated.
5 See SecrLir it tor ,{etails of laboratory er,ahmtioru. These analysis are opttorral hor'r'er-er. ererv eftbrt
shotrld be nrade to collect sartrples for analysis.
6. Salicylare lerels rvill tre thau,u at baseliue ancl tluough Cycle 5. Salicl'lale lelels r'r'ill NOT be
collectetl after Cycle 5. Salicylale le.iets drau,u ar ClDl are acceplable as barelittt Salicylate levels as
longr as thel'' are drarut prior to drug adnrinistration.
?. All patielts. ilcludigg tirose who discontinre protr:col therapy early. *'ill be foll:u'ed for response {or
proguession) u^itlr PSe er.ery l1-16 u,eeks aud fcrr sutvir-al for I year trorn tlte clale of registration
S. PSA rrill be drirwr rT'ithirt I q'eek of lu' ('ycle of Treatluent'
g. The reiearcl llrse u'ill call the patient 2 iveeks alier sia:tiug trretfonnirr to a$sess for Gi tctxicity'
10. T'6e [{&p. ECOG ilrd latrs do u6t leed lo t}e (epee{e(l ou C:1Dl if these rvere cotrrpleled widrir the pre-
snrdl'tirue point.
* pSA shoulti preferabl,v be collected at the salre lab for all tirne-poilts io pt'eletll PSA ilrrchrntioils
15
Protocol


Title: A phase 2 Raldoilrized Discontirmatiorr Trial in Patienls'i!i{h Hontrone-Dependerrt Ri*ing Prostate'specific
A,rige' progressio' Aher Local rher.apl, lbr prosrate cancer Etaluaring tlre s.vrrelg-v of lvletfonri0 Pltrs Aspirlr
7. Treltment Plan
7.1 GenerslConsiderations
Treatrnent will be achuinisterect ou au outpatient basis. No investigational or couxnercial agents
or tSerapres ot6er than those describecl treiorv may be achuiuistered with tlre intelt to treat tlte
patient's malig.nalcl:. Patients nmy discoulinue lher:apy at any tirrre for arl)r Iensor'
7.2 Studr Agent
Mettbmri[ treat[rent r,vill be started at 500 rng twice daily. if no GI toxicity grade greater iltau
I is,eitetl atler.? weeks it rvill be increase,t to SoO rng with breakfast'I000 urg at bedtirne-
which is the larget dt'rse for the reuraiuder of the shrdy. If GI toxicity grade grealer than I
occurs durilg ttre tirst .l weeks, the subject lvill l-re evaluateil every' 2 rveeks turtil resolutiorr of
toxicit-v to gratle less than or equal to I and. then. the nrettbnuin ciose will tre increased to the
*ext close level. lr,Iettbmiiu will be taken with food in order to minimize gastroitttestural side
eflects.
Aspirip rvill be takerr at a close of 8l rrrg once daiiy. Aspirin must be taken with food'
l'Iissed Doses
If patienfs vomit atler taking ureclications. patients shoulcl be instnrcted not to retake the dose'
paiieuts should take lhe uext dose at the sched*led tiure.
If a scliedplecl close is nrissed. patienls should be irtstructed to take the dose as soon as
rerue,rberetl. If it is r.vit6ig "1 hotus of their next dose ttrey should be insturcted to skip the dose
aud resrune tleir u.sual elosing schedule. Patieuts should not tlotrble their dose to catch ttp
missed doses.
7.3 Dose ilIotlifications or Esc*lstions
7.3.1 Toxicitr'
A,y Gracle 3 qr.-1 non-6euratologic adverse eveut. or Gt'acle .' 2 rertal toxicit-r. thought to be
chlg-relatecl rvill leatl to cessation of rr eclicatir:ns. If artl' of these occur' ihe patierrt will be
reutoved ti'om the stlrd-v.
7..).2 Dose Retluction
I)ose rnodilie:atiott ivill not oct'ur for arly reasoil'
?..1 Concomitlnt r\{edications
patreuts ural, take a1y t)?e of FDA approved phannacologic agents rvhile eruolled on this
clilical trial.
7.5 Supportive Care Guidelines
patie*ts ale allorvecl (o receive full srrpportive care therapies corrcouritantly duriug the stud,v'
No other cheurotherapy. iuu[turotherapl,. honnotal caocer therapy. radiation therapy. slr€tetY
for cancer. o, ."1r"rirri*1tal ure<licatioris witt be penuitted lvhile the patients are parlicipatiug in
t6
!'r *: osl5{'}l


Title: A phase 2 Raildorrrizetr Dis..onrirnrarion Trial irr patients $,irrr Honnorre-Depefideut Riring Pr.srare-specific
,turtigen proglr.essiorr ^fter L..cal Tlerap1. to, pro.tnt. io,r.., rtntrrnrirrg the Syrirgy of Metto*uin P1.* Aspirri
tPRI\I.{ Trialt.
i,,,I
thjs snrclv. It is uor auticipated that patieuts will requile siguiticant suppr:rtiYe care' They rua-v
experierce rlfl*sea autl vomitirlg anrl the adururistrntion of antiernetic ageflts to cotttrol tltese
s,vrnptouls ruottlcl tre acceptable'
7.6,JLdherence/(iomPliance
-v.6.1 parie,ts rvill be giveu a rnedication tiiary arrcl ittstructed lo initial it each titDe a
dose is taken. patients ivill also nr:te the tiure tlte dose rvas taken. and if art-v sicle
et'tects were esPerieuced'
7 .6.2 The desiretilevc'l of cornpiiance is : 90o'ii' Patierrts
of compliance will be removecl t'om the study'
7.7 Emergencl' t:nblinding procetlure
Emergencv t'nblinding: In ttre e'e*t of al) elllerqeltc-v' please to'tnttI
phannf). r,(FEEo-pl \.londa1' rtur:ugh Fri<lay belweerr 9.00ant artcl 5:O0trrtt L-'astent
Tirne. For unblurdurg otrtsicle ol:these iro,,rr' please'.*,'ntt IFI.*O:. 
n:tl:"-r.
iushrrctir:u. Remembel", this is onlt' in the event of ln emergenclL-FEse note that' if a
pttient is emergenth' unblindett, ihel' rre consitlered to be off treatment' but shoultl
iontinue to be follorved for outcome evalu:rtions'
8. Toxititl'\Ionitoring and Ath'erse Event Reporting
All patients rvho receir.i one close of prott-rcol therapl' *itt t',* evaluatrle tbr toxrcitl' Each trtotith
i1e ireatrng phvsician riill tullr,o.rus the patieut's crinclition rvttlt respect to possrble tl'eatlllent
related toxicrties. ..\ll acir-ersc- eveuts. rvlrether obsefr.ed t:1, 11r" ph.vsician or reportetl bl'the patietlt'
pgsturi*g ihring t5e iiclir.e porlion of thc-r'apy^ or up to i0 clavs afier llrr: lasl d0se' trf treatt)}ertt rvtll
be graclecl by a uruner.ical sire accor.diug to"the NC'I's couuuon Tenuinologl' c'ritefia ftrt Aclverse
E'ents ((TC'AEt. \'ersi6n 1.0 (http:i,'ctep.cancer.g'-r\ lqportitlgjclc'lllrUl) .ancl recorclecl rn ttre
patient's,retlical recortl. Tosicities rvdi G;p*t.,t -t c,,rtt*.,t ui ttre strtcl-v clata capture plan' The
rype'gra.le.ancltosicitl.attrillrrtioninforruatiottrvillberecorrled'
A preexistiug colditiou is oue that is presenf at the stalt crf the sflrtly dnlg. A preexistiilg coltclitiort
sho*1i onl1. Lre r.ecorcled as au atlr,erse event if the ti'ecplellc-v. intensit-v. or the charactet' of the
cortditiott \volsers dtrrirtg the snrdv peliocl'
8.1 Arlr"erse Event Reporting Requirements
Al aclr,erse exper.ie,ceis cletjireci as any tminterrclecl or abrlolxlal clinical obsetvation that is not
r:f be,eht to tire pntlent. Eir}er the conclitiou wtls txr( pteseut prior Io expostue t(} {lte slrtcl1'
tlierap.v- or it has ,vorsettecl in irrtensttl' or i'eilttettc,v tbllorving exposure to the snrcl-v tlterapv'
rvho calurot trlairttain this level
All "uner1:ec1ec1" (deliuecl beloiv) aurl:or "serious" (clelirretl bek:rrv) aclverse elellts occtllrlrrll
olupto30ctar'salierthelas{closetrftreatrrretlt.rvilltre
Events rvill tre t)rorllptly repofied. in ivriting' tr: fhe local
ivill be ,.titied r*.'iihirr l,l h.:ru's of irritial receipt .f
chu'ing the acttvc- lr.',lLlgg
repottecl to OHRS at
lie rep6r'tei1 to t[e IRB ivithip tluee to ten tla-r-s of ilitial
Protr:col Version E. l')
intbnrtatiott. Ali other SAEs tnust
T1


Titre: A phase 2 Rarrdo,rized Discortir*mrio, Tr,ar in patie*ts rvirh Ho,none'Deperrderrt Ririrrg Prostate-specific
.{ntige, progressirrn,qtrer L.cai Tlrerap;- ro' p'o*t'it co'it"' rt'ntuntirrg tlre Syrergy of Metfonuiil Plrrs Aspirrt
receipt of inlbmratiou. written follorv-up reports are requirecl when actclitional infor:nation is
otrtai*ed to fir[1, characrerize the event. c"pi-- "r 
eacrr ieport se',t to the IRB will tre kept i*
the shrdY regulatorY file'
I, additir:rr to reporting, fo dre local lRB. reporti,g to extenral boclies s*ch as lher FDA rttttst
also occtu.
8.2 Reporting SAEs
E'2 Keporttng )Ar's rn \ -t. ^..." ...r,,-,., 
tet{ rvith the use of the dnrg that
The pishall riotih the FDA of an.v adverse expeuence,ilssot:rn{e:.:!,1::r^1,:.-'::"I'^'j,.,,;o, ar.r*
IJt.t :l:ilii.,:l?i ll:ili..".i. -.".;;; p.,***,r* autl u,,o eve,It later tltatt r 5 cale,dar clavs
---^-. r-.- .....1.,,.i*rorl ^tr FD.{ Fontl
:1,::li$i:l'l'iHJil:f;;il; ;;;i;;;;;;;,-otiricatron *iil'::fli:-"l;ll:i,ll""
Me.l\l' o t.h 3 5 00 -A, ltttp : "'lv$'rv 
fcla g or.l uedrva tc h;'sat'er 
"*i
l' {fax # I -800-r'DA-0 I 78)
Trre pI shail also *otif-v the FDA by terepho'e *r by fac.si*iile trausmission .f a,,r- urexpected
lalel-,:r lil'e-tlu'eaterti*g esperiences. u*ro.i*i"J *fi' tttt ,se of the dr,g' as sooll as possiSle but
no later tha, 7 .alerr,ff day; tior, tle PI'.s tliscove* of t5e evelt infonuation'
8.3 De{inition of Serious Adverse Events (SAEs)
A seriogs atlverse event {expertertce) is one occturing at any cl6se level that restllts in an-v of
the follorving ottl t-:otltes :
, 
Death
. 
Lit'e-tlu.enteniflg- iuurtecliate risk Qf dealht}omthe reactton'
. 
Requires inpatii'i iro.pitatizotion or prol:ngatiort of.existi,g hr:spitalization'
. 
Res*lts in persisterrt oi significaut disatrilit-vti,capacit1,.
. 
Resttlrs iu a congenital auoural-rt'Ibir1tr clet-ect'
. 
Retluires itrtervetttiQn tr-r prevent ol}e 0f the otttcomes listecl iil this defiDition'
Tlre clet-rnition.f ser.ious adlerse event (experieuce) alsr:. includes itttpor"tctttt uedicctl et'dtts'
h.Iedical ancl scientrlic ju<lgrllent rvill be .,**r.t*a in deciding rvhether expedited reportiilg is
appropriate l, ottr*r-*irrratiir,s. strr,lt as irnp.riiot, rrreclical "utitt* 
lhat utay ,ol be irruuediatel'v
life-tlueatening or result ill tleath or hospitalizatiou but.rrray jeoparcljzg the patient or rDaY
reqrdre i'te.eutio* io fr.u*u, one of trre .ther outc.ures lisred-i* trre definitio, abr:ve' These
events rvill .strally t " 
.oorlA*recl serious' f'*u'"pft* r:f such everlts are iutensi'e ffeafrttent itt
ail emerg,eu{.r\' roolll oI at hotDe tbr allergic t or.t orpustn: blootl rlyscrasias or cour'rtlsiou$ thal
ilo uol restth itt hospilaliziltitu'
8.4 Definition of Related Aclverse El'ent
There is a reasonalr.;.;;;ililiry't'at t'e.{mg ca*sed tlteatlverse experiettce' Thai is' the event
is judgecl [:y tire ,,,r*ligoiot to [r. possibly' probatrl-v or clefi[itel'v related to tlte Ientmenl'
8.5 Definition of Llnexpected '{rlverse Event
Au-v aclverse clrrrg, esperience ancltor specificitl" or severiry. that is nt"rt ittcludecl in the cluTerlt
irrvestigator"s brochttre attd'ot package inserl'
l8


Title: A Phase I Randouruetl Discortrirtuario$ Tlial irr Patietrts lvith Honuone-Depertdertf Ri:;ing Prostate-specific
Artige, progressio. etia Local T'erap1, fo,. pro.toi. i'"rr..t Eval*ating tlte Syre'gy of lrtetfon,in Plus Asprrur
(PRI[A, Trial].
ii,'I
9. Tre*tmentEvalustion/Criteria forResponse
9.1 Biochemical Response/progression:
Criteria tirr resportse are indicated in sectiort 4'
9.2 Ctinical Progression
The appearance ;inew lesiotrs on exauri[ation or racliographs (CXR' C'T scan' lv{RI scaut11.,
bo,e scan) *uli rr* evide*ce for cli*ical progression. The developnietrt of syrupto*rs cotr$lstent
withilletastatic disease (i.e.. troile paiu) witha cooctlnent itrcrease itt ret"run PSA frout
baseli,e rvill rlls. be grorurds fo, *u.i.r*ting tbr cliuical proQression via radiog'aphs'
9.3 Sun'ivrrl
Survival rvrll be measruecl startilg t;oru the tlate of entry on shrd,v. Patiettts will be tbllowed
tbr one year atler initial eruollment'
10. Remoyal of Patients from studY/Off Studv Criteri:l
In tlre atrsence ol trearruerrt clelal.s due to adr.erre everlls, treatureut ma.v cr:rtttirtue until otte of tlte
hrbes autl ti'ozett for batched analysis b-v ELISA'
o To monitor aspirin levels irt patients' salic,vlate levels
evetl olltel cvcle.
tbllorving criteria aPPlies:
-a) ilter.rrre,rtllhr"r, tltat preveuts iulher aclliilistratiol of tleatmeut'
b) Unacceptrble adverse everrl(s)'
c) h the .r,*,,, .ri. ou1. cl^rg-related lit'e-tlu'eate,i,g tosicity or laboratotl' at,ton,aliry tlte
patierrtrvillbervif}ttlr.arrttfrorrrtiutlrel.ffeatnrent.
d) batient clecides to rvitltdrarv tlom tlte study'
e) Norx-onrpliattce rvith trealmeut plal'
t) ceneml r:r rpecilic chilnges in tlle patienf's coudition tltat rr:ndet the patienl unacceptable
t.orfrutlrer.treatrrtentirrtlrejtlclgmentoftlreiur,estigator.rrr
g) protoc.l ,,,,olotio, - oro puii*i t*iir* lo have enterecl tltis snrd-V in violatiorr of the protocol
rniglit be drscontiil,re.l tiour tle *ttlcti'at the cliscretioil of lhe Pri[cipal Iuvestigator
h) PSA progrc"ssion atter at least 30 <lays of treatrrrettt (see Sectit-rrr ,1,5),
11. LaboratorY Evaluntions and Clorrelative Studies
These aualysis ate optioual ltorvever' every effott shr:uld be niatle to collect satuples tbr anatysi's' '
fuIettbn,iu trear,reui has bee, repode<l i" ""i "*v 
lor,ver broocl gl*cr:se b*t.als. to reduce senr*
IGF-l levels aucl rnsulin levels [6s1. IGr-l plays air importa,t role iil bofh cellulat nttttaqenesis and
lu,,a* *ralig,a,cies Aspir^in *ra-v inhibit ii* ,"ti".tiou of NF*B. r,vrrich ftrrther suppresses the
expressi.u of n,.r,rr necrosis tnct.ir-alphaitoto-rr"i,terleuki,6 (IL-6) a,tl IL-tp [54] Therefi:re'
irrthisproposeclsnld\,'weflreparticrrlaril,'itrteresteclirrdelenrrinatiouoftlreserturrfactors.irrsrtlirr'
IGF-1. iL-6, IL-lB. .,4 TI.iF-u. eaartiorraifl'salic;*late levels r'vill be meastued at baselure arrd
rlu.oug,h ct'cle 5. Salic-vlate levels rvill NoT be collectetl after c-vcle 5"
o At lraseline. cvcle 2. cvcle 4. cycle 5. cycle 6. c.vcle,8' clrcle l0 ancl ertd olfieaturent c;-'cle'
7.5url of bloi:tl will be cr:llecteil in a real top tutre. senuir rvill be clistritrutecl illto eppelclorf
l9
will be uronitored at baseline and


Trrle: A phrse I Rnndornrzetl Discontruuation Trinl ilr Patieuts $irh Horlnorle-Depetldertt Riring Prostate-specific
.furtigen Progressro[ Atier' LQcnl Tlie|apr1' lbr Prortate c'artcet'E|aluating tlre sy"rrerg-v olNlettbmuil Plrrs Aspirrt
{PRilvtA Trialt.
i,t'I
l1.l Collection :rnd Hantlling Procedures
HooO speciureus u,ill be hauciied by tle Cattcer l,stinrte's Tissrte fuiahtical Selice (T^{S)'
Docunrentation
Please have the nallle. acldless atrcl tlre appropliate laboratotr-. or oftice phr:ne.lttnlber of the
irrstinrtiorr thirt the parlelrt speciuren: rvere'stripp*cl ii'or,. Fo. any cprestit-rus relati,g to ship,reut
I
11.2 Storage & Future tise of Specinrens
S*trjects rvill provicle c6ilsetrt lorleteution altct fitnue use r:f specimetts' At the time of conselt'
sul:iects will tre iltb11le<l that tfiey uraY also refitse penttissiott for fitnu'e research trse of their
speci,rens rvitlrtxrt ati'ecrirrg their participatiou iu the stucl-r- ol'cflre t"ry the health provider'
Speci,re,s rvill tre c6[ected autl processecl tirllorvirrg stanclarcl Biospecirlte'] ]:qo*]to'l' Sen'ice
(BRS) lrrocedgres. itt-.p".inr*ni rvill be de-iclentified ancl given a tutiqtte BRS#' Onl1'
pathological i,.tirl,,ratir'rir for each conespottdirlg blood sarnples rvill be
recr:rcled.
Specimens rvill be slorecl at
Service (BRS). Roottt # 1050
;il::n";';;";,,il;;. 
'ii;1- 
iirk'"tuug rvith dara anc{ health infot:rt,ntion c.ller:tetl folll: t"u'"
prot.col . rvill be reiained fcrr a periocl oi6 y*"t. in the Office c"rf Httr:ralt Research Servrces
iOnnS) on behalf of the principal inves(igator'
12.
l2.l )Ietformin
Product DescriPtion: tablet
Prorluct J rme: \Iettblurirr
Product Dosing: l000urg BID.
Howsupplietl:cotruttercialstrtrrpll'arrclclistribrrteclbl.
Sf o rn ge Req u iremen ts/StabilitJ* : roorll telllpera nu'e
Route of Aelministrntion: 0r'al
Phrrmtcert tic:rl In fornrltion
Atlverse Reactions: \[ost corrunr:rn: diarrhea' lliluse'l'
iucli gest ion. abriotttittal discorn lort artd headaclte'
CiINJ phar:rrac1
:0
;r-1 
,"rvillbent'''
vouriting. tlatttlence. aslheuia'


Tirle: A prrase r Rrl*dor*ize,J Dis.-orrfiruratio, Tdal irr patierrts *'irh Hotruoue-Dependertt Ririlrg Pr*state-lipecitic
Artige* prr:gressio, rfier I-,,,rcat Tirerapl' ti"r, p.o.ioiu i'ancer Er al*ati*g the Syrrerg'r of Nletf<r',i, Plr* Aspirtr
(PRI\I-\ Tlialt.
nr'I
12.2 Aspirin
Protluct DescriPtion: tablet
Product N:lme: r\s1:irin
Protlttct Dosing: 8 Iutg.
Hon, Su pp lietl : corr,uerc i a I s*ppl1, a*it ilistribru *.1 t,., *mlilc 
-v
S(orrrgeRtquirenrents/Stabilit-l-:l'clotuteulperatru'e
Route of Administration: Oral
,,ldl.erse Rerrctions: \losi conuuou: Rash. eilstroirtlestiual ttlcerttions' abdr:uritral pain
crarupilg. nauiea. gastritis. lactic acidr:sis. alcl bleeding.
12.3 Aspirin and \Iefformin Pltcebo
Aspirin arid uretfomriu placebo tablets rvill lre prodrtcecl [:y the Rutgers sclrool of
Phanrracf lnd clixrritlrtecl Lr1' rhlJucf 
'
13. Dnt* Collection rntl llecortls to be Kept
13.l ('rrse RePnrt Forms
CRFs. itt electrottic fbnnat. rvill be trtiiized'
A stttrset of the
o iit,rcl1' specilic data cilpttue plart' i\ll eCRI;s 111]
iu accorclance rvith the imtutctrolls tI)
be con4rleted b,v clinical researclt
il;;;...l.;;il,il;.lli,-ffiTheeCMswilIberrtaintairredirtactuttderrtial
forurat in Ortcore t
lJ.2 Dtt:r Submirsion Timeline *nd Forms
C.m,leti., of eC'RIrs rvill occur iu accorr{ance \\,ilh NCI guideliue;. I}axelirre (pre-slud1')
ec.RFs (e.g.. enr,,r[huen(. urerlictil histoll- concornitant rtreclicatiorts. ilisease assessurent^ elc')
rvill be coruplerecl uo later thar 14 cla-vs atler tlte start of treatrrrent' Treat[rent eCMs (e'g '
c1-ug ad,ri,istratiou. ach.erse e\,euts. cheruistries. etc..) will be coutpleted uQ latet'ttran l'1 <lays
t'ollirvi.g eacS cr.cle pf treatureut. Oft'-treatrnent infon:ltalion (e.g.. follorv-ttp' trest response'
etc.) rvilibe c.',rulrletecl ttrr latet than 14 clays atler the errtl of protr:col lreatmettl'
13.3 Research ('hrrrts
A research charr rs nrai.tainecl at OHRS for each patieut eruollecl. Copies r:f signiticattt strtdl'
sout.ce clocunreuls rvill be tttnintaitted in the research chart. Exaurples ol sotu'ce doctutrent
copies that lvill tre lrailtailerl in the research chart iuclucle: sigrrerl inforrrted coilseill tottn'
documeuts t5at rerif.v eligibility anrl tleatruent ancl docrnneuts that Yerity Grade 3-''1 adverse
everlts ancl respottr.. nr; rrtfomratir:rr rvill tre upclatecl 01r {l prospective basis and rvill be
contideutialll' ntarltatned in OHRS.
:l
Orart"affi


Tirle: A pha"se I Randoilrizetl Discoflrirnrarior'r Trinl in Patier(s rvith Hotmotle-Depertdeflt furirrg Prostate-specific
A*tige' progressro' irtier Local Tlrerap.v to, p.o*tni* i'otr.., f'"nt"nrirrg the S,rergy of Metfo,rri* Plrrs Aspirt'
13.{ Reports
Publicatiorrs arrd
1.1. Drrtl and Safetr' \Ionitoring
15.2 Other Pre-Studl' I)ocuments
Each participatillg cetiter is requilecl
o ('tu'ricitla \.rlee of ail ph1'sicrart "
nrulral reports for s1lrruissi6n tg the lRB Bnd FDA ivill be wrilteu by the
iug the clata captrued on ttre eC'RFs.
i;:1ff,iiiii'1,;l'll,il'lil5r occru i, accorrlance witrr rhe 
-
-ffi;il-i.;i,i..';.,.t1.viitoccruitlaccorr1ancerr,itlrtheffi1.H.I
Data iurcl iat'et1. \loniti:r'irrg Plail (DS\'IP). A,' "initintion atrcl
;.*rj;rr.;"r"i,r,"tir. DSN{P foll-'rrvi,g eruollureut of the fit'st trvo (2) or tluee (3) patteuts'
Sutrseqlent arrdrts rr.,ill occttt' ol] all arurtral lrasis lxior to atrulat IRB corililttilg revie*'' if the
tintlings ti'our rlrt'iniriarion auclit rvere ,.ii*t*.torv- N{ore flequeul -tflt:':l-fil]::'i-*lt":i::
snrcl--v conchrct n'ill occtu if necessal]. Prior auclit tllcl,3rss :11,::-11-:f i::?,,i:l' "1tl:::i:
,ir*;g-;;;.",r,r. "r ir,. rt,,ot rvill deremrine rhe 3ee,cl fr:r, i:i:_11::,::11.i,ii$
All audit
i*.iirlt"t"ifi1r. .1i..r',rr*,1 ,"itj, tlr* uti,"ionl "tl'"ttin'tot o"l t*'ottttl to tl''
15. ltulti-Instittttionrtl Guidelines
l5.l IRB APpror rls
Astlre(.trotc1ittalittg.(e,ttterioratrial.rti-'l,..H]ffi?ix1'!*l!"$:llx.',:ili:.:
patients are entcrerl tril llre trial at a petltctpatttts tltsllttttttr
OHRS rvrll appr,,,r.e tire aclclitiou of each pairicipating instinrtrort tr-r the stndv. A copl'of the iRB
appror,al clocur,eul frour each participaiing institutr.rn rvill be obtainecl b-v the OHRS prior (t)
aciir,otion of the stircir,at tle ,articipati,g irrstittrtio,.
,to ltave the t-ollowirtg doctturents ol file at OHRS
Investigalors
rysiciau lur;estigators (if applicalrle)
of all plt,vsiciart Ittvesltgators
. 
ectio, trai,i.g iorn tll l,r'estlgators
r Sigleci 6restrgntor.ilgreenlent fronr the Principiil ltt"'esti$tator at eaclt participirling celiler
r l{eclical ltcettse ftortt eaclt Investigator
15.3 Initiltion \leetings
A sturlr, irritiirtrrru ureetiug rvill be couchrctecl rvith each participati,lrg ir}stitution prior to
eru..ll,reur r.rl 
'.;iitreurs 
tioin the insritution. OHRS staff rvill condrtct the studv irritiatiort
neetiug irr cio:e prpxiuytl' 16 IRB approvai of the sfltclt' af the participatlrg centel" Itt urost
sit*atious t5e sftrclr. iuitiation rneeting r.vill be conductecl i'ia telecontel'ellce. web-basecl tl"ainirrg
regarcling e-('RIr e ott4:lt'tiort lvill l-re trtilized as appttrpriate'
f5.{ IRB C'ontinuing APProvrrls
htvestigatotStit.rttl1,.iri.i1ioti,,girrstitrrtiorrsurrntprcrr.icleu*ffi,1:::ilIli3Ji}i.l
.op,t.-,it[c'rnstilrrtrolt's al)l)l g\'ed coutinutng revierv clocutu.eltr
Protocol Versiot 8.ll 12,0lilOI:
22
CN.l #:0Sl50l
FDA foul 1572 of all


Title: A Phase I Ratrtlotttrzed Discontiruratiol Trial in
.fuitigen Progressir:rr Alter Local Thelap-v lor Prostate
PI
at ar)* participnting instittrtion ur rvhich
C'entem tltat nre ltpplo\:ed to trtilize the
file corttirtuittg ret'ter,,' docttntentatiol.
l5.5 ,tmendIrrrnl\ lntl ('onsentr
Patieuls lvith Horrnone-Depeudent Rising Prerstate-Specific
Caucet Etalrratirrg tlre Syrerg.v of lr'lettburril Plrrs '{spulr
a crurellt contiruing appl'o\:al is ur:t ott iile at OHRS'
Rutgers tlniversity celitrfll IRB rvill nol be required to
OHRS rvrll uraiutain a cr-tp1, of all aureudurents. collseut foruls and approvals tloru eaclt
participatipg irrrtrnrtiol. C'rxisent tonns will lre tevielved and approved b1' OHRS to elnule
;;;;;i;i;rr.i.1.,'rtli r5e IRB approvecl corrseut. Shoulcl clurnges to tlte prtrtocol trecorlle n:::t:ni]'
protocol alreldrpeuls rvill tre submitted irl writilg to tire
and local IRB for
I,',,.,,*r,,,i.,'i.,l,,,,r.rttu'ttliltitltt:lutlesstlrepatieut'st",*@te<l-Ittt1ra1case.
'- 
' 
-:I-l-
notiticatron tc
aud local lRB lvill be made as sooll as possible'
register patiertts rvith the OHRS central
protocol.
15.6 Prtient Registrltion
All pattents tlot)r pilrticipating urstitutiolls nttlst
Regirrtration De:k. its clescribed in Section 5'7 of this
15.7 Data ('ollection :rnd Toxicit.v Reporting
T5e pI at eacS ,r:trrlti6n rvill be responsible-tbr assrriug that all the reqrtirecl clata is collected
nlcl entereel oulo rlre eC'RFs accru"ateil, anrl corupleted eC'RFs sut:rnitted as clescribetl in Sectiou
t3.
15.8 Dat{ \Ionitoring lnd source Document verificrrtion
If".;';i';:;ii'.iu,I,,.r ,)orlrrorirrg vrsrts t* parlicipaturg irrstinrtio,,:,:lI?::,*::
ffi*, 
less liet,reritlv t6rip et"er1, 3 rnouths. The ruonitoring ..,isits rvill fbcus on lerriv-tngt
eC'RIr data rvrtlr sr)rll.ce tlocuurenls. ;\tlherence to the protr:rcolls). irrcludi[g ttte pro[tpt
repor1i,s r.-if se,,rrs rclverse e!.erlts. rvill be assessed. Finclings of all urouitorirrg lisits rrre
,;:;;;di t;,'" I 
Nlorritors Reporr. rvhich rs kept on tile in the ()HRS resulatr:tv tile'
Issues coucenrlrg shrclr- courpliiruce are ar reqular meetiugr ;; ;; lJI 
rit"'o"
Reseluclr ( )r t't.tultt ( ottttttillc'e.
15.9 D:rta antl (lentet'Audits
I";li 
rrrf i ,-'o,,O,rcr arunurl auclits to participating centers itt accorclarlce rvitlt OHRS
Sta[r{arcl Operilt,rg proceclures tSOpsi. The audit [uicleines at'e ilt nccorclance r'vith the I
I 
.,,.'1 Sof.t.'N{.nitoli,g Pla*'
I 6. Statistical Consiclerations
16.1 Prim:r11' Hvpothesis
T1e ,,1rar1 hr'prrt6crrs is that urettblndu ancl aspirin rvill result irr pet'sistent stable disease irt
patie,ts ra,ilt,r*izetl lei r.eceir,e these urecliciltions atier r nur ilr periotl. By ccrntparlstu patients
lvith rta6le drsease atier a tbur-month nur in period. who are rattdomizecl to placebo rvill
esperieuce a grenter tirte oldisease progressir'rrt
,.)
Plotocol


Title: A pha.se I Rnndontized Disconti.rnration Trial in Patients rr'ilh Hotrtlone-Dependent Riring Prostate-Specific
R ,rig"', progressrou After Locnl Therapy fbr Prostate Cancer Evalrrating tlre S}rerg.v of Metfonrrin Plus Aspirirt
(PRi\{A Trial).
i,,,I
16.2 Outcome l'Ie*sures
Difference i1 the stable PSA rates nfter 6 cljcles of uretfcrnnin arxl aspirul ol placebo therap-v
rvill be calculated iu patieuts who have reeeived 4 cycles of opeu latrel treaturent dr.uing tlte "nut
in phase"
16.3 Sample Size rntl Stntistical Analvsis
Irr this snrcll'. ive hypothesize that patients rvith statrle PSA after 4 cycles of open label tt'eatrnent
rvho are then treaixl rvith 6 c-vcles of rnetfonuin and aspilin rvill have a -1091' rate of PSA or
clilical pr6sressigg colrpared to 80-qo rate of ptogression irr in patieuts lreated witir placebo.
With 2Slrafiegts rapclouuzecl to treatuleul or placebr: the sfntly will have 800'6 power to detecl an
ilcrease }r the proportion of patients rvith progression at 6 cycles tlour 409'o to 80% with alpha
:0.05. Assuuriirg ilrot oppro*irnatell,, l0 patienls pro€$'ess prir:r to randotnization. a total of 66
patients rvill be enterecl ou this shrdv'
17. Human Subjects
17.1 Subject Popul*tion
*-len rvith clinical stnge D0 prostate L'arlcer as er.itienced by rising PSA r,-alues despite have
received rletilire locall[erapy tbr prostate caucer (e.g.. prostatectomy or radiatiou therapy)
17.2 Potential Risks
poiential Lisks to the pirtient secoudarv to netformin include nalmea. voruiturg' cliarhea. and
lactic acitJosis. Potentinl risks tiir aspiiin inclucle peptic ulcer disease and CI bleedrng. These
rvill be niouitor.ecl as detailed in Sectious 6-8. In terrus of the indivirlual's prostate cattcer' tltere
is a risk ol tr.eaturenl rrot lreiug etTective. Futhenuore, il the dnrg rs uclt et]-ective" ttrere is ttre
possibiliry. of clisea.se progr.r*iou (either PSA rising &lither or b.v obselable uretastasis)'
17.3 Consent Procedures
Iltbnretl consent nnrst be obtained plior io couunencittg any research procedtres. Tlte PI slrall
seek such conseul onh' rntler sirch c,ircunslances thal plovide the prospective patie[l
opporhlri6, to cousicler rvhether or not to participate aucl that uririlmize the possibiliry-' of
cc,erciol or pnclue int}reuce. The infonriatioir given to the patieut. or the repl'esellta{ive' shall
be il a larigrmee uuclerstauclable to the sulrject or lepresetltative. The_ ilfonned cr:nsent
docruuettt rlav llor inclucle aoY ercrrlpatorl language through rvhich the sutrject or
represertalive is ura,le t6 q,aiye arr1, of the sirb;ect's legal riglrts orreleases. ol'appears to release
t5e ilvestigator, the sponsor or the iustitutir:rn fi'orn liability tbr rlegligence.
I 7..1 Potential Benefits
The be,eSts of particrlraring in this sftrtly rna-v tre iruprovernent iu a patient's callcer eitlter as a
L[easure of {isease aclr\.it_v gr qtralit-v,:f lite imp;crveruertts.
17.5 Risk-Benefit Ratio
All risks ard beuetjts of ttris rreflrment r.vill be eliscussecl r.vith the patient prir:r to eDlolhuent on
this shrch,. Speciticalll-. t[is inclucles that the patier:t's risirrg PSA value likel,v* r'epreseuls sollle
21
Pr"otocol Ver^siol E.{-) Ll 01,'lU1 -


Title: A phnse I Rmulornized Discortriuuatiorr Trinl in Patierrt.s rl,ith Hotrnone-Dependeflt futing Prostate-Sp*sific
,{ltigen prngressrrrg,i\lter Loc;,rl Tfielapy for Prostate Cancer Evaluatirrg the Syrlergy of ]r{ettonnirr Plus A*plrut
(PRI]\L{ Triali.
i,r'I
miclometastasis. ancl the possibilit-r.' of ftuther progressioll witltout sorle fonn of ittteletttion.
Alolg these lines. the linsic pLinciples of rvhat we Rre hoping to accorttplish with uletfc]nuilt ard
asprrin t,ill be explainecl. The potential risks detailecl in Sectiort i7.2 rvill be uriide clear as
r.vell. alcug rvith *'hat llleastues are in place to niniutize tltese risks.
Alteflrative treetoletlr rvill also be discussed. These options ilclude begiruring artdlogert
ablatiol t6erap.v. uronitoring ot'f therapy. or eruolling iu atrother clinical trial. Additiorrally. the
iruporlauce ottthe knorvlecl5re gaurecl tlu'ougli tlus snrd.v rvill be clisctlssetl rvith the patient.
All rolcl. ruith the court:ilralion of eml:h:yiug proper patieut xelectiott ald study tenttirtaliott
criteria. close clilical ancl lab tbllorv-up (troth of the prostate L'arcer as well as other relevartt
bocl1..s-vstelrs)" ancl rtith the nreclical lurorvleclge of uretfonrrirt and aspirirr are beirrg utilizecl in
patient tr€atmeilt (as au FDA-approvecl rnedication. tor rtr:l-ottcologic nretlical purposes).
theret-ore rve believe that the potential benefits outr'veip*r the risks of the trial.
17.6 Gentler antl Minorities
The Nntiouirl Instihttes of Health ancl NCI
iuchrsion in clitrical sel\'tces aud researclt
rvill govetr publication of the liial. The
subinission ol' use^ unrst ret'iew arrl'abstracf t'lr
Referertr-.es
iuqrot"tauce of gender and ruinoriry
years. Afi'icau Atueticans tnacle ttp
have stressecl tlte
60,ir. Hispanics 6qo. ancl -{.siaus 30,o oltlte
spectrvelv
The percerttage of trtittoritv p,'lliellfs eu'olled ottto
Aruericat. 60 o Hrspartrc" artd 'ioo Asian. respectivel,v.
Siuce the prostate ci:lllcer snrt"l.v tinly involves tlte rrrale population otu tircus of etuolhneut of
rninoritier rvr-rtrld be cltrec ted to tuittorit-r' urale participallls-
No perstlu rlall. on the grorurcls of race. color. or Daiional origiu. tre excluclecl tlour particrpatiorr
iu- 6e clenrerj the lrenehts ot. eruollurent in this prr:tocol. N{inr-rrities ale prevalent in the }tlew
Bnmsr,vick nrea. Therelbre. et'torts to inclutle the broadest possible represeutatton of rninoriry
gr.oups rvill be focustd ou ac.cmal fi'our the corrunutritv as rvell as distaut referlals- This lvill be
accoilplished by courluclirrg educaticrual pro$$arns rvith cotrurnrnity physicians.
18. EconomiclFinancial ('onsirlerations
patients auttor.their rnsurance carriers rvill be expected to pa.v tbr costs related to uronitot'ilg and
tblloiv-gp. psfit-,uts t,ill tre ex1:ectecl to pa], lbr an1'costs llot paid bv their insurattce cauiet.
Pntielts lvill be tespgttsible lirr an1'aucl all transpottatioll tosts.
19. Publicltion of Resenrclr Findin
The policies attcl procedtrtes of
clepat1rl ettt (see: Ilvesti[tator's Handbook)
i all e'o-attthols prior to
rliuical research lrials rvere 70o Ati'it:an-
ffiJnstitute's PI. arid
rttarrtrscrtpt
25
Protocol


I
-1.
4
l0
1l
Title: A phnse I Rnrxio0rizetl Discontiurmtiorr Trial ilt Patierrts $,ith Honrrone-Deperrdent Riling Prostate-Specific
,q,rtige, progr.esrrol Afier L6cnl Therapl: lbr Prosrate C'ancer El-aluaring the S3telgl' of lr{ettbnrriil Plrrs Aspirll
Freedland SJ. Huu4ilueys EB,Ir'{nngold LA- Eiseubel'ger M, Dorey FJ" Walstr PC, ard
Partirr AW. ftr.s& o.f Prostflte Ccrrce,r.lpecific fuIortdit.r'Followittg Biochentical Recun'ence
a.{ter Rudi<'al Prosrotectorin'. JAIr{A- 2005. ?94(a): p. 433-9.
Roelrl KA- Hau Ir1. Rauro,s ClG. Autenor JA, and Catalona WJ. Carr<'er Progressiott rutd
.S1rlir,a/ Rilte."s Follol,,ittgAruttotnical Radical Re.trapubic Proslnleclarrt"l irr -l,J'8
('anse"<'trtit'e Potiettts. Long-Tenn Restrlls. J Urol. 200't. l7-1(-3): p. 910-4.
Krrpeliarr PA. \rtahacler.att A" Reddy CA. Reuther AN{. and Klein EA. {.,'se af Dffirenr
Defitiriotr.s of Biot:lwnical Fnilure nrter Extenral Beant Radiotherap.t'C/rortge.s Conclusions
,4[s,sttt Relatite Trtrttntettt Eflicart'for Locali:ed Prostole Catcer. Urology. 2006- 68(3): p.
593-8
Freecllarrd SJ. Sutrer NIE. Dore-v F. aud fu'ousou \t'tt, De.finitrg tlrc lde*l (;rttpoint Jbr
Detenrtirtittg Pset Rattnt'ence a.fler Radircl Prost{tlo.(to,ttl:. Prosrare'Specific *iigen.
tlrologl'. 2003. 6lt2): p. 365-9.
Widrxrlk A. Klepp Or. Solbrr^g A. Damber J-E, Angelsen A. Fratrsscrn P. Lrurd -I-O.
Tasderrrir t. Hovei \,1. Wikluncl F, ancl Fr:ss{. SD. .[rrdoo'iue Treontteul, triilt rtt'tt'illwul
Rcrtliotlrcrnp.t,, itt Locnllt .4clt:cyx"efl Prastute Coucer $pcg-?tS.fito-3.t; .4n Open Raudotised
Phnsc lii Trint. Tlte Lattcet. 373(9660): p' 301-08.
Yang \\'iind Leviue AC'.,{rrr*'ogens attd Pro,slole Concer Bone !$etasllses; E"ff€cts ott Both
thp St,*l rurl tlrc,tol/. l:ndocrirrol ]l'{etab Cliu North Aru. 20I1.'10(-i): p. 64-i-5-i'
Serrrga B. Ocana .{. ancl Tarnrock IF. Dnrg Re.si.stcurce in !{ela,stotic Castration-Resi.stanl
Prostrtre C'ancer. Nat Rev C lin Orrcol, 20f l' 8(l): p. l2-23.
Heenrer.s H\,' aucl Tindall DJ. Androgen Rrlreptor' {Art Coregtiotors: .4 Dirersitt: ttf
Fttrrctit>rts Catn'ergittg ort urul Regrilttlittg the Ar Transcriplional Cottryles;. Eudocr Rev.
2007 :8(7): p. 7?$-808.
Sarker D" Reiti AH. \'ap TA. and de Br'rrro lS- Torge.rirrg lhe Pi-)k,'.lkt Patlnt'a.t'.fitr the
Tre(ttnrt,rtt of Pt'o.strrto Crtttcer. Clil C'alcer Res. 2009. I 5( I 5): p. 4799-805
yoslilroto'M. C uuha IW. Ciouchy R-A", Fonseca FP. Tor"r'es CH. Soares FA, and Squire JA.
fislr -Jrrnll.sis aJ'10: Prcst(tte Concer',lSlrorm' Thnt Pten Genonir Deletion Is Associated
x,itlt Patn'Clinkrtl Otttcartte. Br.T Cartcer. 2007. 9?(5): p- 678-85^
Sclulitz tr'{. Griglard G. N{argue C. Dippel W. Clapesius Cl, h'fossong .I. Nathan S'1. Giacchi
S. Sclrerclep R. ancl Kieffer N- {:,trtrylete Loss af Pten Expressiort os a Po.:;.sible Enrl.t'
pl.ogrtt"t,stic: tr[arket. .ft>r Pro;tate Ciilc.sr l,Ietastnsis. hrt J C'ancer'. 2007. 120(6): p. 1284-93.
Atrrerr-\Irrrtin Ir.IT'. C'hari A. Palladilo AA, Craft NA. and Sarvl'ers CL..rly'ltogen-,lctivoted
pr.ott,in Kirtttse Kittoye Kitto.se I Acti,t",crles ,4nrlragen Rece.ptor-Depentlenl l-r'rtrrsc:r'iption onrl
^Lp<tprctsis irt Pro.srtte C'rtncer. N.{ol cell Biol. 1999. l9(7): p. 514-1-54.
Di lorerrzo G, Tortora G. D'Amriento FP, De Rosa G, Staibano S. Autorino R" D'Auutenlo
N,I, De Laruentris \,I. De Placiclo S. C'atalano G. Bianco .{.R. antl Ciardiello F - Expte"ssion oJ'
Epitlerrrtol {irotr,tlt Fctctot' Receptot'Correlote.s with Disease Relrtp,se and Progres,tiott lo
,4rtrlrttgt rr-lndepetttlettte itt Htttitru Prostule C'urrter. C'lin Claucer Res. 2002. 8( I 1): p' 3438-
44.
Traislr A\l autl \{orgerrtaler A^ Epitltnnol Grov,th Fnctor Receptor f.rpressror Esutpes
.4rrrlr.o{prt Regulatioir irt Prostctle Crutcer; A Potentinl Mttleculat'sttitch-fur Tnnott
Grovllt Br J ('atrcer. 2009. l0lt 1?): p. l9'19--56'
8.
9.
l2
13.
Protr:col Verxiol 8.0 I:,'0lilOla
CNJ #: 081501
l ,l.
l6
l
6
7.


Tttle: A Pfinse I Rarrdomize{ Discontiruration Trial in Patier(s rvith Houttone-Depertdenr Rising Prostate-Specific
A,tigen progre:rrt.ru After Locll Therapl, lirr Prostate C'ancer Evalrrating the S1'nerg.v of lr{etforruin Plus Aspirur
tPRII\IA Trialr
Or'I
15. Yardl'- GW auct Bren ster SF. ltrirl Srgrrolllng aild Prostttfl C'auur. Prostate Caitcer Prostatic
Dis. 2005 8(2): p I l9':6.
16. Aarouson DS" N,hrller Ir{. lr{eves SR. Clurng WC. .Iayararn G. I-verrgar R, and Ram PT..{tt
Andrg,qert-ll-d-.5rol-l -4tttocriile Loop Re-Rorrle.s fgfsignal in Proslate Cancer Ce//s. Nlol
Cell l:ntkicrinol. 2007. 270(l-2):p. 50-6'
17 . 
Koulelrs fV autl Siegel RD. lfelforntin and Cnncer; ,\:err'.'Ipplirations.{or arr Old Dnq.
N.{ed Orrcol, 2012 J9(21: p. l3l'l-?7.
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2-l
Protoc


30.
31.
-15
36.
J.J,
-1_1.
34
Title: A Plnse I Rrrnrloruizetl Dircontirruatior Trial irr Patierrts t itl Honrtone-Depertdent Ririn;r Prostate-Specific
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38
-19.
+0.
41.
the
-'l -1 -
:8
Protocol Veriort 8.() 12:0lr?0li


.12.
43.
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|PRI}LA. Trialr.
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.t4.
{-5.
*6
47.
.18
jt9
50.
51.
53
5.+
52,
56.
l9
Protocol


Title: A Phase I Ilandonrizcd Discontinuation Trial in Patients with Hormone-Dependent Rising Prostate-Specific
Antigen Progression Aftcr l.ocal I-hcrapy for Prostate Cancer Evaluating the Synergy of Metfornrin Plus Aspirin
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70.
Protocol Version 8.0 l2l0ll20l7
CINJ #: 081501
30


Title: A Phnse I Randorrtize,l Diru-on1i1ns61ior Tlial irr Patieuts 'n'itlr Honuone-Dependenf fusingr Prosrare-Specific
fuitieen Progrei:iou Ahel I ,rc;il Tlierapr t-or Prostate ('aucer Er,alrratirig the Syrerg-v of N{ettbnuil Plus Aspinlr
{PRIlvlA Trial)
i,,I
Appendix A
Performance Status Criteria
ECOG Performitnce S{ltus Scale
Gracle
Desctiptir-rus
0
Nonual activirv. Full,v active. able to carry'ot)
all pre-diserlse Derlirnuance rvithout reslricIiou.
I
Suuptorns. but arnbulatory,. Restricted iu
physic ally stlenllous a ctivity. btrt aurbulatorv
and able lo cany out rvork of a light or
sedentilry ualru'e (e.g.. light lrouseu,olk. oflice
u,ork).
1
ln bed d:50ob of the trure. Ambtrlatory arrd
crpable of all sell:care. t:ut rmalile to cal"l'\i out
alv r"-,rll actir:itre.r. tlp and about utore thau
)0o u of rr,akiug, lrrrurs.
ln bed:r50oa olthe time. Ciapable of onl_v
liurited selt'-care. contined to bed or chair urore
than 509i r:f rvakitg hours.
I
I 00o.o beclriclden. C"onrpletell, clisabled.
C'nrurot can1. o1l an1'self-care. Totally
contlued to bed or chair.
Deacl.
,1t
Protorol Veniol E.0 1:01/'?llll

ICF_001.pdf: 
Metform in Hyd roch toride, n Jnrp"i- " frurt, r,e prtiu.t,
with Hormone-Dependent prostate Cancer That Has
Progressed After S
or Radiation Therapy (pRlMA
ICF - Main
L2/01./2017
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P.,\Id I tx .\ RtrS[..1R('t{ s] I:n\
l'itle of Stucl,v: A phase a Rfindf,lulzerl l)rscultiutration
Ri si' g Prosls te-Speci tic A*tige* pr,.rgressi or: Atier Loca I
lhe Svne'g-r' *f h,ferlbr,rilr pl*s Aspi'i, ipI{.Il..{A .IrialJ
I'riol in P;ltlents n,rth Hrrrrnone-l)epeucleut
T'herapt, For Plosfate {_'aucer Evaluating
Principol Invrs(ig:rtor:
[ 
.orr**nt.lbrur. is palt cl' lu iulir:lred l:ouserit pror*ls tirl a resear.cfu xtldv *,d it rvill progide
itrlatntatiott (hnt rvill ltelp vurr {. d*.',1.-' nh*rher r,r"lr rvisli *.r-"r,rtn,t**;;;;'d;;;;sesrch srnd,v. Il rvrll
help yc'tr to uttderstaltcl rvltilt tite slurl! is aboilt nrrt'l $,hilt rvill happen iu the tl}urse rf the snltly..
Il'yotr have qtresli$ns at any-titltt dtu'ittu lhe lesearclr study. v{}u shoulcl {e$l liee lo ask lheril arrd should
expecf to be sive& au$wet.ri ilrat !.ou c*uipletely unclerslauti.
AtieI all of yoru qllestiolls ltave beet ausrvered. if yr:n *till lvish to trke part in the sludy. you rvill be
asket{ to sigu this infanrretl conseut tbru.
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You ale not giving np arv of yriur Iegal
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rithts lil'r,oluulecrint li,r thii r.esg111.g|1 slrrrlr or lrv slilrirri_{ tlrjr
fhe
litl. .
The costs lhilt are usunllr
rl utlr
111,1:01
covereel irtclucle thiugs sttch as resealch latrorator"y lests retluiretl hy tlre st1d1
Page I ol td
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Prcgreslir:tr Afrer L*ctl Ifi
arrd ths costs of cnlrecrirr,g ail urthii iuro'urafr*u rc{rurr(}d tiv the strdy.
lthy is this stutly bring donr1,
Recent rnedical sciettce sltgcesl* that 1*'* FDA oppr*vecl r*er]icari,,r rnetti:mri, (*sed to treirt t{ialrelext
arrd aspiriil (used t* Irtdveltf lteart atlack*) rttitl rl,-lw the gro*1, *r'prostate crncer rerrr iu trre rab*raton,.
'we rvart tr: luorv if givrru *rertturrii' a,ti"aspirir ;; ;;;;i; rvilr sro*, trre growrrr anel p.ssrbr_v kr,
prr:stille cancer. cell s,
\1'hv har,e you hern rrrkeel ro t:rke grart in (hir studv?
tcsl ltscrl lir llli)ltllrll l)1,,-Iitl., ..,,,,..a,
\liho nrrrl'tllie ;r*rt in this rtudr...) -"tnrl who tnlr, not,.)
l'r)u tlliily take 1.lnrt nr rlrrr :trrtlv Ili
r Yolt nl"e il11 lldttlt rtlill*' ls r,'en;s ..lllge o, ol(l€l'. r,r,lrri lras ber.rr cli;lgn*sed x,irlr pr.(rslnfe ci.lrlcer.
Ill'ostiite stusie:tllr 1t''lllrr\(tl t,rs i1,. urrtrirl tr*alrrr*rri ,,tlo..r,,l .p:trstnte i.:iulcei .,\ rrrrrru IlS.,\ rr
detentrirrt'r_liir,tlrrr,r rltllcri:rrt lllriislucllt(nt.,,t.lrS,t rlrat i",iru,"r, al ierrrt , ;,,;;;r';,;,.i'",t
r 
-l-ltere is rtr-r eviilrrlee rlt ltl\, l.)l(lrftte ti:ulcL.r uu (. l.itirtli tr,hr.rnt] salurr
\.'urr rnal Nt:rt tlrkr l)ilr.{ rr) llrir ,lrrilr.rl.
. 
1'our p'rlstfile cilllcdr"lrils rl.lrrtri urrrlrir.le the prosftle.
r Ytitt ltavc iutolltct. t\,lrc ul.crrrrccl ,
r 
Y,.Ir iue Clllt.r.rtllr, lakruq ulcllirrrrtiil ttrr ehtrl.retes.
r 1'*rr ar. crr,rrrtrr'rakrrrg erllirirr rirr h*rr.t <rrsei**.
t 
\'()u hitt"c itltcl'tth lcr(l\t'(l sr'tttc lirtttt rrl-ltutttt,rtt:ll lri:rltmr:ltt ltrt ptrrrlitlc (irICr:r .
r 
\-rrr lre rakirrq n,;u liu irr ,r1 ;1111. [rlrrt.rrl llrirrrrer
r 
Y$tt iire f;tktttg il ur)n\l!,1,)t(liti lintt-rlttltttrttiil:t..r,tirfrs {NS.,\lD)
. l'ou lrnr:e it hi;ttrrr- ol stouitrcit hleetlus ol rrlcel r.
rvtllrrlro irsk \'ou rrrh,.:r rltrt,sliilus al)(!u{ \'r)lrr r}t*(llL)nl lrish^rrv in
tirrr.lrt,lr
How long will the s(ueh, trke nnd horr nr*nv
'l"lx rnrdy rvrll err*ll apirr.utinrilrelr, 66 patiurt\
AII xubjects rvill take pffrt iu fhrs studv nr the
11:htr will _vou be :rrked tr: rlo il"r'nu tlke ;lrrrt in thir resenrch stue[1,..)
r
\ *t-l(,n,i.ri: I I {}l :{r.l -
l)av* 2 iri I6
I'he stuily doclor illrl,'or resel,u.clr lenrrr
order lo make srue vcur cjraltv lii bq jil
rubjec tr n'ill ptrticiplre,.)
Pllitrrl 1:ilr tieiyutt irrlt tr il])ilt {)}.itrlirt cjr" I { } 111,,,,11r"


!l1l(i!' Iiiic. A flir*re i P-ru':ilt:ttzsli L)r(!:+llrl:rri'1i1t)ti it':r'ri :
Pi,:,u,e.ri.rti..\ltgr ['{rir'l flrur.ri.r I !]l lr1"'r.!r; ( 'rt'rtl I rjllli;tIlllg
-
Ouring the studv:
If you decicle to particrpnte ott tltis sntdl'
morlth ever1. dn-Y firr li:ur iltolltlls' This is
Befort st*rtin g trtutm*:nt :
yo* rvill tre asked to c*rue ter the clinic to have screening lests dolre tLr tind ort if ,vo1t cfill be lI] tlte
snrdy. The results of rhere testr flre u$ed to ctetennine if y,:u ere ahle to go sn this stucly tllxl {re paft of
,*g,il* callcer rnre. The scleet]lng tesrs include the foll.u,'ing.
Screening rtill ctlnrisi of:
r 
Sigrring titis ittiotrtted (()llrel)1 li)rlll
r 
yr-lu rvrll be rrskrcl;llrirut \,,rlu lr*altlr rrrcl rtt..tlrcnl ltt.tillr'. \'*n $rl1 alril tle l.k.ecl al:t'ttl ;'lttl'
tlt*dir:ttiiltlr \'\rtl all'o I *klrt g.
reslttralotr' ;ttlcl ltclt t ultr"'
r Bl,i:d reilt {lr[trrrl I lflr>p,r,rltr \\lll he takett ti'cittt "''t.rttt rt*tni
,) ('olulllulu bl*,rtl crllllll i( If(')
i 
C'lreuri*tr.t tesls ti) hclyr eleterrtrire h*rv voru kicltte.ri itlxl h\jet lre litltcttc'ttirr'-t
,., PSA lt) ltldllltor \'r)ul (llsiiil\e slalill
c .{n \lRI i:r C'J'rrtitu trl:\'ouI hr,rlt ttl utclttitcr t'*ttt tlirellst'!tiitlls
,. ,\ ('l'i( rrilrlrrrlr-,rl '[()it(rgl ,tl)lt\) \eall is il slrlih'ttsittg x-t;t., 1l,'['ith iit t)l]t l)ill-l r)l'\'r!tu'
i:oilv.
t-; ,\rr \lll"l i\lirguutrr Rrrrrrrilure lrrragiug) ir intagrrrg lltitt tt:cs a sltlrttg lllilslltlllu ir*kl t':
loilk at ')lle 
pill t tll l"tttt trr:tl\'
r 
Ilrltte scart r.tt'1.1111 lrorre tr, nlt'rlrl\ll tl'llte 1ltoslitl('t'illlt'{l ltilt rFteilil 1{) \'{}lll'lroltfr
Il is r,ert,i*r1;i.rrt;t*t flr,,l rrrrr rrll tlrc .t11ilr.sltlirrl':rll rhe rn*rlierliottr \'o11 at{ titktttt. 'I"ltru itrcltrtlc' bollt
illly quesli{}ns ahrrrrl rrlher nrerlielltr)t]' \rr!ll witl]t lo take tJtttittg tltt rltxlv.
irt Pltiertti *tlll ll*:ttiltte'l)rpert'lelri Rl\itlf Pr1)ililie->l]etillt Arrtigcrr
t h< t1-rrerlt3,ri l{er f,r::trirr Plt tr "\r1>rli:r 
L ll'lt l i\1'{'l"rir l }
vlri \\:11l h* it:ketl {l titk* 1\\'{l illllqi. ilrl-}11ll) itltti tttc{lrltttitt br
refent'tt fr) rt: the Rttn-In Stltgt" '11'tlte -'ltttlr'
\',-ru q,ili fake *tre 1l ) "-\.pirirr Sl lrr:r trrl:lcl tltil-r"rt'tllt lil.lii \letlirt'ttttlt treattttettl
il l i(10 rrrg trt'ic* lt d;r1' 11 11!1 lirr)ti If ;lfir'r' llr',r ueekr' vr)ll (ltr liol llil\'e itllv
llfllrrtil. r,oirtrtrrrsithcu rt u,rllll* lllClc'ir:crJ trl 5t)0 tllg.\lllllllreilklilrt;rrrd ltXi()rttg
\'*rr rvill he iltottit,'lt't'rl ."ritlt l:lr"rlil 1t:fr lttttl 1ltrn'ricnl exitl:l\ \rvrr\j filtll t'eeks
takilg fhe rfrtclv tltltgs lt: rlesctllrerl b*li:u'. hlosl .f lltere lcst: itre rr'ittlttte ltticl
1111g .rf rilbiccts \\'illl unllcrt cttclt il" )'rrlu r
r lleftrre rtllltill. lltc slttrlr tllc(1l..i{i.ll: r'r,'rrt PS,'\ levc'l ri'rl} l':e tltttketi.
u"ill be :t;'ttleil ill luls
l,;trl .t,1,.' ullctl. r 1..'-
;rt l:ctlttttt* tllltlv
lbr llrr' 1rr'l irrd \'trll lll *
3te l.)iltl irl'llt* llL)lllllll
-Ihe PS,\ ,.l',11 nl"r b*
:('l'


-
checked lurtlthlt' rvhilc vorr aru rerri\iirrg slrrdr. tl*atrn*rt.
Plii sicaI exilurilriltien
Vital $isns {bl.r,rri pr"rsslue^ hciul r'nte. letiplriltt}ry li}l*, ruill feru}lgrilnllcj
I,Ieasrrre r.*ru' lrer*ht arril u,erp.ht
{-ip tri 3 teilsl;lr,..tts..i-rll he takeu fiirttt vorrr veirr rrr nlclsiuc litrx'r'orrr kichrer,r ancl lir.el nre
trloeitl cells arrrl plutele t-r ille rlr.rnrrirl.
' , Bl.rurl \iltlll)lrs tllitv l)* litkttt ttr slitdr,chttrl le',clr.il'alr;rh'z* bl(rcheuile al rttnrker,
R*tord:iuv srcle *tlbets vrrlt iu.€ htvurg lirrur tlie snrdr.uiedicatic,u
a
a
I
a
tttirsed n da)ie ruithin,1 ltltur,rf ttrte lnre vc)u weLe *lrerlrrletl tr.' 1akc. il. \'()n rllir\ tak* thc tii:se nt flrrrt
lirtt*:'ltttl tr.rtttitttte rl'itlr tlrt ttcrl tt:gttl;rr rr.:hcrdtrlrti rLrrt'. II"rt lrirr lre.:rl (t*it111 llrlln.l ltolu.,. "krp tlu rio.r
ilrtrl citlltllul* u'ttlt iltc' rtcrl qelretlrrl(rl il,,.,t'.
.\llct ciltttplelurg l(i tr.',-"ks ()l'llr'irtlrICnt. yrlll t,rll lrar,c a l:)S.\ lrrc'l rlrar,l'rr l() crrl]rlri]l'(f ti: tlre PS..\ lrrcl
lirkett b*l'ore )rllu \farlerl the slrrelr'lrealrueltf . l)eperrclilr.$ r.rrr 1]re le5ults r',-.u riill either.
;l) ('Ontinttc on the tI'e,Ilmr:nt rli(lt m*tlornrin ilnrl lnpirin lrr.u;rrrs* \'r.,lu I)S.'\ llrr tl*urerrrd lrr,
luore fhall l50l lrl*ttt'lsetl hr,- t,tte tatrntlt. ltrl ulslltrtce tht PS.,\ Irlrs rlc'clrtrle.l lii:rrl l{tng uil, 1,,
7,5tt$..:ttl" ) tlrttpattil tu thc l:a.elute valrre.
Ilircontinur trrlrlnrrnl it\ llnt't of thir ttudv l;tturrr. r"our P\A lrar ilrcr.:lstrl lrr rnore tltilrr -i{)(u
cotttltareii lrr flte h;trrlirrc ltrlrre 1-ollr di)[tor u,iil cliscrrsr 11[rer llr.rterrtial t]elllnlt'ltl\ \\lth \ou i,
t'r.rtt iliscr.rtttlllud tlcitlluclll ii\ Il;rr I rrl'tltri slrri,lt
(lontinut' trerrtnren( in the Rrntlourizrtion Stlrgr rll' lhe rtuclv Lr*cau:e t'.'llr lla\.e n i)SA ler,el
500 u.
In (he R:rndotniz:ttion Phrtre \'olr \\rll lrt irs:rsuur.l bt,clrirtcc l* *lie r.rl'lu'rr lrnrs rlcstrrbr'rl bt'Lrn'.
ttiedicltlir.rttJ rltrittu tlti: itrrrlttrtt rrl llrr'rtrrch'. Ilris i. r*lbrreil ttr iir it "rli.rrrhle bltrrd" slltrl\',
AR\I l: (Jrte (1) Aspirrn tlnrs tnltlet per clitv aud uretl'.inuiu tluee 5{)t)rug tirlr}etr elailr'{orre rahlet iu
llte tnrrtttittq aud ttto tltlrlc"tr nt lr.'rltiru*1.
,4^k\I 1: {)le il.} placebn as1:iriu (a tab}et that looks like ai;pirinl pel clal.'fitel })lacebo ureti'onril* {a
t*[:let tirat lcoks like urelt'orruilr] rlaih,{one trblet ur fhe rn*nring ancl two ralrlets at rriglrti.
b)
cj
']lr'ittlltr:ttl ilt lltr'trtttrl)ltll,/iili!r1) pltit..l xrill crrutirnrr, lirr rrlr lir {i rtrrlntlrr. J)ulinu
bu checkttl ltt(ullltl\'. l{eF.arrll.r'.,rl'rrlrieli luul \,(-)r.l Lrlr iu. it'the P5.\ iuclca'er
ernttqlle it ittcr*ir.e" tir)ln l{}rrg rrr[, 1{l l5rrg,rrrI. i tlr*rr snrctrr. tt'rjl1t1rlellt
(i\.],,tI
\:11(]|)ll(l1l!: 
I 
i)l -l'l
P;r:e-l ol 16
tlris tirrrt'),our PSA llill
try rn*re than 500'o ilirr
rvill be cliscontiuuecl.


e, i,"{',,,i i,,t:..tit,r,,,, f
lliett rlt* rlrtthr lreillltlol]{ \\'ill ho rliruoltlittttetl
.{.t e*ch l'irit. the $trr{h, tlocttr or rtttff ttttv tlo iln\ (}r :rll tl'the follorl'ing:
r 
Piti 'ical c\illllilliltlr'll
r 
Vittrl ,ii.rrr. {},1,,,,,1Prr.:rlltt, lr..,rtl llrtL. ld\l]llrt()lV l.lt( ,,\lal tcllll)t'lillltle]
r 
Nleasrtre ,r'*tir lteiultt attrl u'*iultf
r ('heck Yr-rltr IISA
cell:
. lJltioil slturl:1e. iluir"l:* lilkrll lr) rtuih iLttg ler,els. rtt ill)ith'le 1.ri,.:,':1tttI}ir:lil lltarker-.
r 
Recorel artr iitle-el'lects \ rlrl lre ltrn ing fttrttt llte rntlll' tueclicuf i0tt
r 
ltr:1)efi1 (- i rtr HlLl seirrrr; tl \.(:U lt:rr,i: rvrttpt,.)1ll\ 1hfi{ \'r}lll lllr}stillc cill}edr l}lilv llil\c slleail
.\lier cotttpletittg lreilttl1.111f lolt rri1l Itltr'*.
r 
l'lrr':te.tl (\iillllll;lll')ll
r 
yitll sigltr (lrllt'il ptc\rll1't' ltsltrt r;llt l!:\l)ilitt(\ll l:11( t)tltl tetttllelalltle)
r 
I,1r ltl I lcrlt:l.lrrrrllr i.r1 lrllrlr11 11'1|| lre '"ititrttt lirt r*ttlttlt lt:sls
\\'h*t *r.e the r.irkl :rntl,:rr tliscomfortr vou nriglr{ experitnct if l'oil tlkc F:lrt in this qtu(l\"'l
\\ihilc $ll Ili* slrriir'. \oil iire irt rlrt li,r rtrr* riilc *ller:tr rl-rrr,":tiherl lrc"ltrtr:. It'tt nltiittk[ r'lirults: llrcse rvlth
te{eil,r'r.'rtirer r.l:trgr t,: nurkc srtlc ctleclr ltlsr:r.rit.rtrr iltrcl 1.r., liturI}It(}ltllirl*. \lllrt}'rrclt'elliclr r$ 11wll\'
s5orlh,ntler.clelrothel.irl.rr t: rtrrp],rr'rl. l:luf rrt srtnre ciiies. lttle eftects ci'ttt 1->* scrlolls r-rr [iti llueatetttttg'
lotts lit.littu {)l' l){ftllil)}L'ltl r't Iitlal.
Riskr of metlormin:
r \lilil gilstr(rlllte $ttttill *r'tl4rlrrttls {l}x}\l ci}lllll}(lt} I uttt ttl' ltl)"
: Diatthei't
,, Nxttseil
, 
\:rit]lillllg.
'', Esce:xit'c rlits
treiltl)letIi. CiilsfLrrurtestrnill rrtle et'lict* cnrl lx)ssil)l)'be avotrlecl i1'rtiett*rtttitt ts takett t{tllt ttteali
rtabi6zeri rxi iui)"rlirse,.il'ruelli,r'urin. e.rultl be ilue ttr lactic it,":iitr,:l: trl dlllel \cll!ill\ clireart {:te lit'Lru'!
r 
l_actic nqjdosir l$ i., \,er' l,ill.e t I 10.0(x)) hul serrous c$ull)licilllori. thn{ itlletl: [:r.rtlY ultettuiltr';lttcl
that cnu Lrccur due rrl llleltllullirr ircrrr:rurlntiou dttlirtgtreiltntettt. The 1:t't'setcr'of-lnctic rrticltirir c;rtt
pirrrelrt ,i,1ce i.t irrrti$llr cintira r\rII|.)lrrrll$ )lrlrilxr lrl 0llter'(olnili{)rt 1,:tthlcttti ttte it l't-* s.rttllls 1l1t'd
hi l}r*re ldvattceel cit\es f)t lilttir lrcrtltsrs. tltere rrt:rv l)e ursocrilterl exllellle ll'enkltesi r'r llte{11}c"sr'
i'.::It:{)i:{ 1-
I)atc 5,ri l6


a
a
.
a
-
rllCh i\'ltllltOn}I ilnd lrru lllr-rl nrllll'\ th* (1t)tl\)r irtrrilerjlllclr i1'thev (,{cnr. l^*c{r* nctclosis is ir
rut*tircrl enlergenc!'llliit rrurri lie'lreirtetl irt lt,r11:ttal. 11"1'rrrr r.lcvul*F lirclte ltcirl*sis ll*1 lirn11111 5|lottltl
lre eli sc rintnilre cl irlhuerliir t e ll n uti pre1s1111*rr11t'
Filliqirr i l - lt) r,ul ol: Xi)t) pltir"rrtr)
lleadachr" (I -10 i.)ul trl I(llllrrrti*nfsi
\lctallrc lirrle l,r lir.i,l.,rtettlrlllg 
lll rll)l)lrl\llll;llclr 
\ i,ttl (\l'l{X)1';rtiCrtls
Skirt leelrtcss. 1r*r'r: rir'rr
i{ it kr n t' r} \ Jril'{xr :
Itret * ;t*ti rril"i{}u\ qirlt' r'li*r ln
r 
Itlcreittecl lirk uf'bl,:erirn* il ii lrtc. l.nrl lnlp{-tftanl s}de etLect *lirr1:rrrtr 'l-ittr t" ntrtsl ul{*u reen rile:
rlf bleedutg r; in fhe gilstrorrrtestinlrl lrirct {rtonrach. esrphauus} x{tere lt rtlii\.he'iissoctilletl rvtdt
10.0()(,) pdoplr trr hirr,e selit)rls lrlrrriirrg iu lhe rlourilch Fer ),ral t)liter titclrrtr rltch i'l! \{)tlt it!lt'.
\\clgltl" use irl'ci.rltir*tlci:rrril rnir1, 1rrtlllcl1!:r \'(]llr tisk rl'rlcvtl,',1ltttF \f{ltll;lell lrltci'lrrrg
o Dirttiage lo tlre lirrrrrs rrl-thc rttrrrreeir i.rrtri errrph;lStts u'ithrrnt ltldcilirtg ll]:t\'{)culx txleh'
ller Yeiir.
r 
R*],u's svtrdt*trte lJ ir lrre hnl \rn('flrs cr,,rtditi,-rti llt.itt ciitts*: su'clhitg rtt llrc livcr llttll trrstlt. Rtye's
sr,nrlr*nre rurlil utiell ilt"teci: clrrldr*rr ancl tc:ertRqers tec$\'rrrlts liirttt I viri'rl itttcctttrtt. tnlst
col)llr)olllt tlrr: flu or clrick*nllos .,\rl)ilrrI ttse lt,ns heerr lrnlietl 1\'rth Revc'\ stttrltilttttt. Il.ele'o
{ it}fluelrza )
Rare iiucl prrteulialh' serroll! ritie cl]'ects trl.lslluttt are
r 
Slrrrtrircli ul)ret
r 
Dtlrlrltr'a
r ('oustipalir,l
r 
Rarh irrtel ltile:
r 
Allersrc relicllolli x'itlr li|. l"ete and tlur:at srvellin"c lltat u:ay cau.ie ditftculry bleathing
in this silld\i ilr"e
r 
L{eart aud trli,,"ril \'(s-\els: lllr'gulilt heilrllierlll. l*g sruellirru. lorv blr,trrtl llresstlrc. ltst lteilrl rate
c Brain fln{ilterves: "{gitiltirrn. lxanr 'wellit}g. coll}a. crrnlitsiol). tltzz-ittesr. fatistre. lteat{nche" hrtllt
lloilv l*rrtpc"r'nlru t sle*pirte sn
r filartrlr: lrigh bL:orl susilt. lrigh hi,,oil ll()til\\ll.llll
' 
(.iilltrolltlertlltiil: ilr)lilrch llllrct' slrrtttlch plitt' ttattselr' r'trtlitlitl:l
,t:..',,f
\'.-rsl.,rr Lllric ll rll :{r1 -
I)irs* 6 fri l6


\lr:.ir 
] irlc .\ !'li''c - l-l rri i 'r'tt;c I I)t""ri'tr"r ';1"1' ': "' :t' i''"rct"'
l,r,.lr...t,,tt.\ltct I \,a.rl llrut.ri, l.'t i't., '.'r; ( l,{.!l I i titt'rttt'i !l'u \111ull}
-
c Riooil: l,w reil hl*iul cell r:ouuts {nuernin). ltxv pla{elctr {ue*ded 1* ltilp trlc*diig). r;kitt l:ftstttg'
iurbilit-v ttt stitp irle*tlirrg
r I.rver: irrtlarrrrnatiolt \it the ltr,'ct. datttage to tlte ltver'^ itltrt;lre itt trcrrels *1'ltrtt 1:toteills iil the hlilr:d
r 
Brrtte: itotte destntctt,:tt.
o I{trscle: trtltscle ht't'itktlc'n'tt cirtt:itt!. kttlnel' rlntttage' r'r'eakltcsl
r !I*uirtg. lteattttg l,'r:r. tutgitr$ irt llrt" t;rts
r Kichre-v: r-lecreirserl krrluel, liurt:tr*u. iutlauuuati,-iu iu the kidne-v- kichrel' lailul'e' kiihley pairr
r Lrurgsi: rvhe*ziilg.. brenlhing tirsi. rLllictrltv bt ealhin$-
r 
Nuse: l'lllulv ll05e
Ilisli *f lll*lrtl l.)t:luillg: 
1 i 
, .:, .. .,
*rth !{c,rrrr,.rtte.l)e1t:rdelrt l{i>;tig liti:'rt:rlt-spetiiic Atili:c:i
,.r: I'lell,rrrttill iltlttr'{rl;tt rtt rP}'1111'{ hi*l I
x"prtr{ed ilr x relttli r:l'lil* dl't'
I{.iskr of * }{RI St*n:
Yitrt ltlitS' I*ul c l;lrrttli:;ti i'. :l't'.:
riltllitt*il }i]"'i*(. "l'IIo'ri: i)lt Ilil
ri tll lrr' ttrlr'et*rl 1lt!t' lll{ '" L"ilr ,
;ulil in *glriitr lt*lxLtlt*l'tt
{.}t itti\li}tln r.ll'Y{}11tlt:r\ ltll.'.',i1\L''ltiii':i 
:'t'd itll*itt 
jl1}lll l!'ltl*' 111 ir
l,]1,r!-r.r: *i'i*r{s titiur *>i1:L:rtxf t{r lhr }ting1}(t1{ t-r*lii' 
.l 1t* t.rtrir:i1 i;g43{:;Jr.'*
itlrij tlr;i\'(i1trr* !'r.)ti lp ixl.rtt:ti,:ttti Itiltrtnrti:l' lt.:gi.lll*1t*' ili'll llarir*" 1!1:-'r11q'r:i
('rn 1'ott t*ke otlttr merlicincs lvhile on this rtudr")
1r: gr-r uu takirlp tltere ttteiltcitle '.
to tilke.
Are thcrt an3'btni:litl li.rr ltru if rotr chotst to trrke pllrt in tltis rtrtflrch slutlvi'
'l'hsl.c lllil\: ()l"nlir\. ll()t lre ilrriue l urtrlii.'irl lr*rrclil tL) r\)tt [iorrr tlrkirrg l]art 11] tlti: strrtlr '
I'il;,;H.,.,Ir'1-
l)ar* ? rri 16


!iriri1. litle: A Plrrrre J P,rri,J,.rr:ri;:rLl l)1..\,nrrj:liiiiiou llr;rj:
P:(,:lc1\rr-i!.\fi*r 
I.L'c;tl ]-lut.ri.\ L,1 1,i,,,!.rl; { ,,r..;r I r;ilrlittilti
-
lhe lirtrrrc.
r.!1 Patldllts 
'.,, rtl: I-{*r'lli:ur-l)eper:ile:il Itirrnq l\.trrare-!p*ciiic Arrriltcrr
f Ir \l'rtrr::t ,ri \lEtl"rxtjrr i]ln. ..\r]rrr tri iPl.L]\1..\ Ir jrrII
\\'hnt
At tbis
During the cottrce *f the study lrilll will he updated aboul ally llew ilrftr11latiorr rlar
)'oll ilre rvilling t{) so ou takrng pail ill the shrrly. If new inti:mrati,.xr is leanret{ rhat
the stutly or.vclu t'ollorv-up is conrpletetl- yr"xr iryill be conracte(I.
r!"e \'our rllern*tiIes il'r'ou rlon-l lriln( to (*he ptrt in thir stu<1r,1)
(ime' thete is no uttiversalll'acr-:epteel standalcl freatnrelt ful y*orr iype olpr,'rsfate cencer
Il vmr
. rlt itrl'*fh*r Fl*,:iciart *f'rr,r,, .ir..,.',0;rr*.' f:,.,,,,rr*r:r,i,r, fr.'"ii;ttllii
Z*loclex {treatrneut to decretse the level of testosterone ir your tr*dy or to i
z{}loclex {treatrneut to decretse the level of testosterone ir your tr*dy or to irtertereivitlr the *,n1..vri'r
body uses festosteroue). nronltoring r,vithout treatmenl. or other chnicatr tr:ials.
3't.rrr rlecrd* iJ'f,i,u n.rll taku parl irr thrs xturlr,. \'r.rrr iir.t:
illtd\:,. llr,orr tl*cirJe tlnt l.orr du tlol urslr to tnkc 1:art rrr
f irue.
I'alk to your d*rtol about y*ur clrr-rir:es [:eii:re
turcler uo *bligation to take l)flrt ill this re;earclr
thrs stnd-v*. v*u are ti'ee lrr leal,e the rtudv at any
Ilorv u'ill I'ou linfln'if ner,'infirrttt:rtion ir lerrnerl tlr:rt nr:n'rlffect lyhetlrrl. 1'ou sre wiiling lo star.in
thir rc.se*rch sturlr".)
rrml'atl'ect whether
runl' aflecr \,(}u aller
,lVill there bt *nr.cost to you to take p:rrt in thir stutlr,,'
standart{ 0f care- as \rotl woulcl ltave receiveri rhese services eveu ii"-yorl luere uot pnlticlpat,lg i* r}ris
snrdy. These prcceelures irtcltrde dr-rctorlAdvauced Praetice Nr.ure (APN) r.isits. rautiue lab terts
{coruplele bloeid colults. cheutittties. and }}SA.i. and restugiug chest x-rays. 5rlre a16 ('l il,flll srat}$.
You will be respottsible t'or srly co-pa)'nteutx chre li:r otlice viiitr^ co-irr$nl?rlce$ ancl tle<luctitrles due cur
itttY tests an#tl proceehu'es that are reqrrireel and c*nsiclered stapr{alcl care.
stucly
to nrouital stncly elrrrg (aspinn) Ievels rvill [re paicl tor b,v
If you have any q[e$tiolrs *lrout insru.auce col,
iuctr, cir r.vliich laborat*rir or facilities vou are
umde availalrle to,vou upol] l't,{lllest.
er'fl!Ir. iuclnriurg iln\: clllt
allerrved to have test$ r1t.
r:f 1"r<lcket ell)ellrL,$ ,v()rr lrilght
a financial corurselor ivill be
llrill vou br p*irl to txke purt in this stutlr'?
Yotr *ill ttot be prirrJ tlr vurrr lrrrlicrl:llrr:ir iu this research stutlv
Hon will information *hout l.ru be kept pr:ir.ate or confidenfiall
confidentiality carurol be gui.rrarrteec{.
Yoru persorral health rrrlirnrmtrun. rcleutrflers aucl research dnta are
tINi;r:f
Versrorr (litlc: I :,01.:r!l -
Page I of l6
collecf ir:ns
steirerl iild ketrrt ilr r seclue area iu the
The
1he


Irilictesrible
!turi). Title: ,1, Phtse ; Fl"al,j,:,rtrizecl Dir;ottttrttrrrli*u Tri*1 lll Pnti{rllt v'ith ltro|rrrnru*'I)e1:erliiefit
Prr,rtcr-rrrrr.\ftcr1..'i.ri 
llr"r,r1'rl.':l't'"trll('rt'crIl;'lrt'ttlll-!!ru\\t1cf91 
ll\1ctl"l:l:ttli'lrr"'\'l'rrilr
-
(. trtrtprrtSt sCIe.til\ cr'rlllillllilli{ llullpl}ill llclrltlt rrlttrttlietr ittc
ili.)i,:{rtr iu}d le*olu(h lelttll ltill htvi'l dtrer':1 aceeri'
11'hnt rvill hnppcn if 1'ou nre inirred €luring this stntlv?
If vorr take pariilr rhri srucly. vou rr,ill tre es1i"rse.1 to cerlaur risks of pel'sorlal ittlLrtf ilr ndditrcxr to tltr:rse
assrciated lvilh rtlltttlitt'il tiltttt. r)t Il'rillllrcllt^
rn$ti,1I l)er.sLlilirl irr.yrule. ur lllr)r.5se) rr$ n direct ronseqlrerlce ,-rf pillticlpatii-)I1 lll {he research' 'I'he
subject's healrtr irtslrattce carriet *r otlter thirrl-part-v llalrel' lvill be billecl for the cost of this treatmeut'
colllpen:atrou rvrli L,;";;;.t";il t " ,tt* I 
:rnel no *thei type *f irssirtante is *vailatile ti,rtr rlie
I
lVhat rrill h*trrPen if 1'ou
thc ;tutl1'?
Pnrticipatiou iu thrs stnclr''
nind al llnY time,
If .'-itu do nat witllt 1rr elllel
rvill rr*t cltange. atrd v,"rtt
olherwise elltilletl.
Yott tttay also rvitlrch'aw vtlllr collsellt lol
.\nua lren^at"i(addr*ss proviclul orr ptge l)
. 
U
Riting Prortate'Slxsiiic S"lttrgett
iPRIM.{ Tritl)
do not $.ith tn takt Jrrrrt in the rlutlv or if Tuu lnttr dt'citl8 n$t [() st*r' in
11rr' use of'l'uttt r"lniil. btti vrrll lllllrf il* tllit itt rl'lttitlu ttl I)t
ls lilllUllilt)'. \'litt ttt;tl Clteteire Il()l ii) llill'llall)illL'{11 \()ll tttav ChAtlgC vi'ttt
tlte rltulr.t.,t rler.:id.: l|! 5[r!i] l,)itllle l})illlIlu. \illlll.c'latiilrtsltill ri,illr lltt llttdv rlitlI'
,ra' cltr \r] \uith.pt peuirltv l,rrril ruiih*uf lusr rrl'bettelltr fo illticlt \'{rlt iils
ilr{lrvt}Ttaattxe there tttar'
e are requlle
Filre F,rrrii ;tIttl f)r rls .'\dtnillislI aIioll
Iel)rlrt irnvtluttg
the :rlcl-v clocior. can x'ithrlralv -votl
relnted lo llte sttrcly. if Yon ueed il
,vou rlroy llnrre sltt'fered a research
, not [:e al]
hcwevet. t*
to llu
ilre dat:r
lhat relates to the saletv of lltese dtrtgr
ti ot,li. t1r it. \'!)ru stllrh.di)ct()l cill) \l(tl.l trc)iltrII*1Il er.err rl )'oI tlfir il i11iils tr: rl;tt' ttl 1lte iitttlr
arleliriorral lisrt lirr rstetv Ielir)11s.
Also. yott should ttttclet'staltcl that the S1:ctlt*or' itt consttlt*tiott u'ith
i"r',m ihe stucly ai anv lirne tf vott tlo uot tolLxv the ii)$tlllcti(lrl\
dilfertnt lreatilIt'nt. ot il'vt-rtt ltitve I sltrily-related ir'5ttry'
Who tr*n ,vott call if 1'ou htte *nv qurslitnl',)
If you have atly.1,r**iior,. irboril takitrg l)irl't rt} tltig strtdv ur it vou fbel
lX;;,t:io1;:,r,:
Pare 9 of l6


lnril1' frtlr: A Plra>e I Rar:,llr:'rizerl i)i-'ciitttllitlti':rtr ir-ui :
Plruter:ii.ltt -{lirt [.-+c,r] I-i.r*r,ri.'] I ut l'r'.''t tI( ( .!li!i, I v;lhr;rli:llt
I
rcliltr:tl rnful'v. \:'rlll {ill} cllll tilil \tu(l-\' ([(]ttor:
lu Prrf rerrtr l'. tlh Horttri.rtt<'I)el,ellrieirl
: rlrt tlrtgru] ,'1 1{trli:'rrltilr Plttr "\r};it::t
Riring Prottnte-lp*ific i;rtigcrr
iPRIM.{ Tritl}
qnestirlrts ahtrul
fl$ a tesearL:h srrbiect. you call cfl1l
\\'hrrt nre \'our riglrtr if vrru rlecirle to (ake llrrrt in this l'eselrrclr rtrrelr"'l
tbgl upless )/g}u irtr.e hltl lr ,-"[nuee li,r itrk {ir^lgiitir.rl}r arlil hilve tree:t gii,'ett lttI5\vetl l,-r all i)l r,"'rttt
qllesll0ll}.
Protectetl He:rlth infol'nrrrtion
aurl r-ulates i,-r at leasl i')llc r)1 llle lirll,.lrvlrtg.
-. 
The iuclilrchlrl": pil:l Irr\Lr1)l .r tttllllr ph-r'iicn1 or llletllnl hcnltlr
. 
'I'ite plovirir-rll i)1'lleilllh Cill* lrr the urtirt'irlnal
. 
The Ilitsl. plessllt or tltfitte lliil'tllelit lirr healtlt c;ire
I"iie ue:it le\\r.pnragriillirr frll 1,111 i1[1ruf lrcru, \,'olil lrerlth iltf'onlati*l rvill Lre llseil (rr tltsclc:ser'l 11r the:
l)r'l rrrll;l I tttltrlltt;tl trrtt
please read thls iirthrr|izirtirril rc-ctir.rt) nrrd the couserlt lhnrr ra|ellrlll'. Ark illlesti()1)\ if anvtltitig is n$l
utl(lcrslnltrlablt lt, *,'ut t.
-,luthorization to use ]-our health infornr:rtion f$r reseAr(h purpose$
Because irf'orumtiou ;biult you i'rrul \,orn'health is persoral elrd privnte. it gerrerallY cturl*t L>e used trt
tlis research stg{y rvrtfuo1i your ro.ritteu aulhorizatiorr. 1l yotl sigr] this fonn' it *'ill 1:r*virle tltat
clixel:setl irr t6e stud1,. y*ur irifi:rnuiltir)r will *rrly be uxed iu ilccordartce u'itlt this auth*rizatlott {irrtrt
and tlle irrlbrrrrer1 colsent forrp sncl x* requirsd *r allowed bv law, Please I'ead it csrethlly'hefore siglrirrg
it.
I)o vou hnvt to sign this art(horizrrtion ftrrnr?
You do rt*t have tr: siSll lllis llutltut'ieiltir.rn tornt. iJttl ii'-vorr do tr:l^ Y01l \\
tlix researclt stntl,v i.tttr.l retetle alll re.{i*lllClt Iel:lte<l prodttcts lluw*r
csrrd.itiotl for receivittg ;lll-v nledlenl care otltside the su-tcly'
(1NJ*:!
\:erriou dale; 1:,'01 :tf I -
Page l0 af 16
ill
et
utl lle al-rle lr.r patlieipate tu
"tuttittu lltu li,ttlt i\ ll(11 il
1l{Ll Dilectot


Sndy- fitle: .4' Plrn*
Prc,gres:i*n,{ftel Loc*l
"irrli in Pttr*rrtr i,, lfh i{t,t:tri.ittt-Dei-rerrilerrt Ririrrg Ft*ittlie-l|ctific Ariligell
rllrrlurti tL( irllergt ,ri }'lcrl,:::l:iIr llltl\ .1\|111:1 iFitIl1'.\ l lirll
Pr"irreipal Invesligator
If yCIu sign, can you rel:oke your authrlrization or tyith{ht$'Yottr inform*tiun l$ter?
If you,riicre to iarticiprrte. \\lu ilre fiee tt'r withdrarv your ilulhclrizatiorr resilr(lills tLe ttse atrd clisclor;nre
,.rf -vppr henltll iltbnnnlir,rl iarrtl tu di*r:,:tntinue fllly $lher psrll{ipalioll lx tt}e strd-v*} Rl {lIlY tiille^ Aller
arrir 1gr..*,i6u. yolr lrealtl: irrtonrultiou rvill uu lottger be nsed trr dirclosed in tlte *tucl1" escel)t fo the
was provirled l:etbre von rvitlrcke\l' v(,lu arrtli*rization if necessaly t* rilflitltilin integriry of the research
r)l' if tlte rtata had alreadv heeu xtt \:perl o1'all identitier*.
l1is rlrrrlr, )"oli llil\.tt(i rr.r t1 tirilrrrg. lrr, cirntlrclrus. flte -'ltttlr l.rrirre rpel ittr'*sltg;tlqrl .
r*'hat personnl inform:ltion will be ured or rlisrlosetl?
yo*r health irdbmration related to this snrd-v rnay be rmecl or rliscl*sed in corutectiCIr with this tesea:clt
irrdicating o, .*l*tirrg to a parficular medrc;ll couilitiou. blood attd otlter lisstte rarltples and r-elaled
records. physical exalnil*tinnii. x-rilvs, L.[RI's. *1.. ]'oul pelxr:rtt*l identrt-v^ t]rilt ir your llallle. addr"ers-
and other iderrrifiers. r.vill be kept coirliderrtifll. You will have a cocte il$il]ber ailrt your acnral nante rvill
not [:e used. Onl-v vonr siudy t'loctor rvill be atrle to link the t:r:de nmnbel'to !'our llill]]e.
ynur 4ala n*y lre irserl i1rcisurilir:1:rr[:]icntionr. II"t]re lindirrgs li*tu the *fixly are ptrtrlirhi:d. 1'otr t'ill
1ot be i4eltilied lry uaure. Y,-rur rrl*ntiry rvilX tre kepl cuu{idenlial. 'l'lte exceplion tr'r flris rule rvill be
rvhen there is a c*urt orcler' or rvherr a inr.v exiilt* requiring tlte study dtlcttx' to report cotrmrutticittrle
diseases. In tlis eale. yolr will tre ilfrirrned of the lnterlt l$ <lisclCIse this iufbrrnatlotl lo tl:e state ag,etlcY'
Such a lalv exists in ilierv Jersev for chseases such o$ curlcer. iufeetiotrs tliseases xuch as hepatitis. HI\''.
vimscs attd umttl* otherr.
Ieg.ulallLr' i geuctc\.
relrclioil tcr l]re sturl)'chrrg.
l{ho m:ry urie or disclore the information?
T1e followigg parties are nutholized to use and,'or disclnse yoru'healtli inlorrnatiott in contteclion rvith
tldx r:es$arch sttrdv.
tIRlS-t c()tlrlllttee
i
t
Ievler$s rescal'c
t0 pr0tect peol
p&rtlclpitllllg ill


I
Who nrrrv r(ceil'e/ult the inform:ltion?
-l'he parties listed in the precediug pl{rngrap}r rnay
pelsonii arld organizalroils ibr theu' use ill collllectl all
r LI.$. Fr:ocl nnd Dnrg Adrnittistrntion (fDA)
r )ialtotal ltlstttttfe. *,1Heliltlr {NIH)
r 'i'he Ollicc.tirr Iiurrxrn Il.rsrar.rh I)rulec{ittts iOtillP} irr the [1.S. I)r:]ritltlIi*lll
I trurtiiltt Setlicer t DI lllS t
your iufi:*,ation urav be re-elisclosecl (sharecl) tr-v tlre recipietts described *bove'
requirecl by larv r{r protecf the privac,v of the iutarutation.
\Yhtn rvill 1'our *uthorizrtion expirt?
Your autltorrzatiott rvill expire 5i5 l'rjxlr illiet'
y*rn' shrdl' data u'ill be cleslro-veil'
rtlrh' c{lllll-)ltltotl. .\t tlli' littt'-: tlt* ltttk hcllvtett li'lt iltttl
ttrisclox* your health iufurnriltitril 10 ltr* tbllowiilg
with this research xtuelV:
ol' IL'altlr arrtl
rl llttl' :ife lla)t
Will access to Yrrur nrrdir:al r*cor:cl bt limit*el tluring the *tud'v'l
.[o mairrtaiu the inlegrirl. ol'this resealctr stucl.v, yon rl]sy ilot have nccess t$ fluy ]realth inl'onuatir:n
cleveloped ,l$ pfifi *f this stucly r*rtil ir ir conipler*d. ,qt thai poinr, you woulcl ltnve acces* (o strch health
inti-rt*ati*n if lt were *secl ro urake medi**i o, billing clecisic,ns nbottt yott ntrtl was iucluded itt yurtu
otlcinl medical retortl.
Where cfln Iou gct morr informationi'
Y,,:u tttav tall the Natir.rttitl ('nttc*r Ittslitttte's (
\.'ote: l-800-'1-(.\N( ER t i-800-{ll-62-17)
'alICet lrtibrttutl it.rtt Serl'tce al :
(irllcd't. uu lr; j:ilil, -!;liJ
t ltr'
Yuu rnay also visil the N( I \\ieb site
F*r NCI's c:linical trials inlbrrrtatir"ru'
For N('I's gellerflI irtlirrrrxrtiott atrnttt
p* to: ltI!ti-,,.i.:ltucgl ti:.:,i:Itl:if lj-i-i lil:
vou il(] II.)t
rrehsiles and ritlter itrfirnnatii:tt
Consent to Stnre Tis.lue $nd llefilth Informntion for Future Resetrch l"lse:
The irlrestigiltor is asking yi:ru'perurissinu to sforc any left-over bh:ocl specitrrens fcrr fitttue resealch
snrtlies. if _vou agree. the"sittirrirus lvill tre kept ancl nmy tre use<l to leartt utorrr aboul ciillcet' Yotr nral
stlll partir-:ipnte i, tle rnaip st1il1, er.eu ii1,'ou cio not agree to alluu-1'*ttr specitttert' to tre sttrt'ed {irr
luture retearclt.
Horv and where wilt vour tis*ue and henlth information be s(ored *nd by whonr]
iii* u*urpt*s will6rl kept urrtil the1, are u;ed ttp ar de*fr*1etl. 'l'he snruples are givclt a c*tle to
protect yourpr-lvacy beirr" the--v aie usecl. Au1, relatetl irrt*rruatir:rn given to rexearchets rvill also
be coded.
a c0lllpll{el
iil
ilii\,r-t ;tCCC.:' l(! i] l)f l \t)lllll cOllllliltUI . \'()ll ltlil\ il{Ct'5\ l]lt'ir' '
irt 1lte l{tst,ttttc Ittlrl i.tillrtittg ( cli{{}l iin tlte secr'llti1 l}'lrit'ul'
l1{1 Ct^}\l f1t \'1}tt.
ll-"1;,,t,
1)lrg* ll iti l6
ll I :l(r I


iltril' Iiilc: .1, Phare I F.rri;!rl:rizerl l)t(i{)ltulii.ltiorr llil} 
:
Pt0grctrt,.rtt.!tl<r l-iluirl )-iru.t1,., Ii.,r Pr,,rt.rr,.(.,rlr.{r l.\:rlri;:!tll}e
I
Ilre saurples aud ltealtlr rrrfirnrntiorr rvill tx rforecl
lu Pll:slt: r.,,rllr Ht;"r:r*li-De1>errilelrl F.iiirrs Fr.ci\lrte-Spc*ific A*irgcrr
. flir -\r.:r*rgr ,:i ^'tlerl'lrnri* Illur ,.\:;.ru:,rr rl,l.ll\1..\ 'l riril l
$s,'lg|,,'i11rl\'\clvlLc {l}l{S} ,JILS i> rr lrr:rre hirnk
I,rrr.l 
l,,crrletlo,ff
lloll u'ill tissue Ernd inform:rtion bc collecterl?
$nldy pl'ocedures. Any' leti-over saruples rvrll he pr'*ce$sed and trnltrl'eu'ecl ir the BRS tixsue balk. Nr:r
aciditronal lrloud sp*cilrells lvill bt r)eliected tor st*mge at]rllirtule trsr'. [nl'rrnnalilrn Ijuu \,olu rnedicfll
record ll,ill tle collecfed. hut r.vill llot cnllfairl ftrly personal intirnrralirx. Aly related urfrxnation siven to
researchets will trc co(lt:d.
l$hnt *re the risks of h*rm to r.ou?
Use of Your P*rsonrrl Informiltion: 'l'he grealest risk to --vou is l'elease of 1,r^1r irtlix.uraliol fi.our
yoru'health records. To reduce this risk ,vllil'nanre and persoual iuf*rrnatiou lsuch as date pf
birth or nredical record rlunlber') rvill n*t be uxed. Ytlru sanrple* will trc corled ivith a stuily
itlerllilicntiou ltutrber lo protecl \'our Fersonal intbnrmtion. 'I'he ilatnblses {evelopitcl t"irr tlris
plo"iect will be secnrecl nttcl onlt' the stnd.v drctnrs ancl authorized persorurel rvill har,e access tp
il. However'. people rrtnv clevtrlup \\iri\:s ur the lirtrue that wotrlcl allow soureone lo llnk ytrul
rlredical iufonualiott back to vurt" It is also possible the computer svsten* can [:e ]rncked bv
rutatrthorieed peoplc" l\re will do our best tn 1.:rclecl veur por$otral ink:rruati*n.
Rirk of Gtnetic Testing: \'rrur spe,rinrerrs will be rued in the frrnre t* le*nr mr:re about horv
to l)rcvettt. diagnose. lleat r:ancer arrcl ruay'be used t'or gerrelic lesturg. f]re results ti'om the tesfilg
r.vrll not be placed il Yoru rlrerlical lecortjs and nsed tr"rr rese*lch r:nlv. y*u rvill uor be c*ntattedor
1g'cgl1:g' lhe resrtltr ii'r'ull gcl)eltc t*slrrrg.
Although yonr genetic irriorruatir:n is unique t() vou. you do share s*me genetic inlbmration rvith
ye[u'chiLt'en, parellt.t. brollters. srsters, aud other blood relntives. It umy tre possil:le that genetic
intounation fi"t'rm thern coulcl be used fo itlenti{v }rr)u. It nm-v also be pr:ssible that genetic
i:r{trrnratrun fi'r:rn you currld trc usetl to irelp itletrLily th*nr.
New health itftrrrnati*u al:rout genetic traits that uright at]bct vorJ nr yom bloncl relatives cr:rrl{
lre forurd drrriug a researclt slttd\'. \:ery rarell,' healt]: ut' geuetrr intbruration c*nld tre urisusrd l.rr..
health providers. lile irrsurarrce cnmpanies. and others. For example. lilb inrurauce cornpilllres
rnay cltarpte a higher ratt basecl *n llris inltlrrrmtiorr.'fhe rixk ol rnisuse ul'your gr:uetic
infonnatiotr is very srnall. I'lris is lrecause the researchers lra:i takeu specinl steps trl keep your
intbruatiort nttcl resttlts er:ufielertial. lhere are $tflte autl lbcleral laws thal pr'otect ilgainxt qeuetic
discrirninatron.
Gcnetic Inform:rtion [,arv: '['here is r ledelal lau, r:all ilre (ienrtic lrilbtrrstir.:rrr
I'{cutdi;criluirtatiou Act iUINA). }r gt'rreral. tfiis lag, urakes rt illegal lbl healtfi iusuraltce
cotupauies. lirollp ltealth 1:laris. artrl urrist *nrpluvers to cliscrrrnirlflte ilg1{liltst you basecl oll your
genetic irfonuatiou" This law Setrerall-v will protecr you iu the i'ollor,viug rvays. il) heatth
:{ill


Pr irlril,,rl !t'e\ti.jnlrlr f
"qellrtic ittfcrtrtriltieitt \l'ltett tttlkius (leclsii:!li r*Fnrdirrc lr:rrr cligibilit\: or'l)l'ellirrrrrs: arlri (ii
el.tl1:litl'Crs r.vith l^( qrr nl$r(,errll"rlr.rVers rllit\, llr.}l ils* \,$lll UeUeltc tttlirnttititiltr tltat r.le Set lirtrtt
tltis researcit rvltett ntakitts a decisitru to hiie. pron,rit*. orlflre \'olr oI 1,6err r.,1iug the fe:.:,s tri'
litb iusultrrce. dtluhilitv irrsru*rrcu. r.rr loug-terut car.e ilisru.lulur.
'l"ltr.rc nls* nrrrl lre t>llrer llll\itc)'rrrl,: tlrirt t.rrc rutkn*u.ri.
\\ lr:rt lrc lhr hentfitr ul'prrr.tie iprrtion':)
tttil-v lrelp irnesfrgalr'rrs trntlerrtirrril. pru'ertt. r:)r lrent th* dis*:rrc-, il11el crrrtelilifrrr strrruccl irr llre ]rrrruc.
Hox'n'ill infornrltion:l116tt( t'ttu rtntl r'our tircue slnr;rler lle kellr prir.-lte anrl conli6t,nfitl'.)
d;tlt trl'lltttlt. itr.ltIt*:.. i,] trlllt'] l)t'1:rrrr;rl rilurrlllr'rrrg nriirrrnirlrorr. rill rrtt 1x, lrrrketl rr.itlr thc
sirutpl,,,s Vdll {iYe
lr therc othtr im;lrr'{irnt inf*rmlrtirn to cnnrirlel.".)
('ort
'l'ltere i5 ll{.1 t(}s{ I\\ \'i)ll t1'r'0tt i1grt'e t(-\ lcl l.ls l,r sir]r't] illt(l lt\e \r)tll lirslre nrril rrtlitrrttilf:Ort Jtrt.
lirrru'e re:*nrclr
ittlirrrttittirrlt lcltls til ttlitklltg attl tltttu. 1e\I (lr tr*itltllrnf. lllerr,is ll() pliltt 1o rltlr1e srry i,llire
l)rttlts wlth v{}lr.
Whnt rlre Youl' rights if you ilgrr( lo the rtorlgr lnd use o[ vour tisrue lbr futur.e resear.chlr
)'0lt ltave the right fo ask qttesttotts abrrut auy lJlrt of our st*rage alcttirlrue reseuch af uly tir*e.
Yr'ru should nol slgll this krrru ttrtless yorr have a charrce lu llsk queslronr antl have Lreeu g5'*u
alls\vers to all *f l.orrl qrrestierrtr. \-r,ru pnrtrcipatirln iu stonrrg tltulr)r.tissues ur rhe BR$ ir
volullfary. \'0tt clo Ilot hfl\'c' lil pal'ticipate. Ii.vill r1r.). voll call chatg.e voru nriud al au)' tlule.
lYhat sre the procedures firr withclrtwing consent?
We rvill keep receirds linking yolu idertil-l.' \.vith fire tissue sfiorpler lbr a p*rincl *f I tJ years aller
tlte sttrrir.' lias Iinishecl. If at al)' ttule vou decicle !.'ou rlo 1o1gel' wfiIt votu sgtltples lsed for
If Your sotlples and rtttbrrualrt.rtt hilve ah:eatly beerr used tbr reseprch bel'rrre volrr re{luest. it rvill
l'L15eitl !'i]^
1\''r't tr.
r,tll lIIil\:'il
lllIl fo
i ?lrrli l)tl'S(
llilvale
110r)
!i{^rtt lll rl\'l


il:flffi**1,#;15ifiil:;:;',,,::; 
il-r;;;i"s;* syne'gy'i:f r{etlbrrrrirt P1*r Arpirirt iPnr}'1'{ r.i*ri
ruot trc possillle to dcstrrrv thern.llrrvrver. i:nlv tntus*il sptcitrtens rvill be d*str*-vecl' \'tur
1e*lt5 irfor"rrrilti*rr rvill rro lorrgr:r'be trsetl fcrr l'esr:ilrth.
P$mission to store l-irsue tlntl llealth Infrrrmrtion for Futur"e Rese*rch t-se :
please tell us if and hex, vuu ,ovish vour sarnpies anel iltfcnlurion fo be ttrecl tbr ltrture research'
Initinl next l11 tta) r )'orl i:rrrgut 1ot.tt sittuples artd irtfcxnati*lr ti; b* ttserl^
tr.{y sarilples ggIL iutbrmatiorr rtray lre stareri atltl user] ftrr fllhrre research
r,tii,,,i''
rGREITIEYI' O
I ltrrve reacl fltts et:tire tirtltr. ilt it ltl:ls hr'eti te;'td lr'' ttle'
tli*cttxseil. ,\ll ilf nrv (ltle\tiull\ lhrrttl lhir l*r'lu al llur
1 itgttc lr: llkt llnrt irt lltrr *llttlr"
N()
i;;i,'il'
PARTICIP'd-tr8
nnti I 1:*lieve tltal I ttttdt-rst:rttil r'rhnt has i;c'elt
sltrrlv ltilr"c [:u:ett itttr$-et trl.
Sutr_lect
Sulrject
Narte
Sisnntrue
l)ate
IIOR ).i()li-Hl*{;1,ISII SFHAKI (i S[ lBJIi{]"l'$ :
sign*turc of Resder/'[-ranslutor If thc subjctt Does ]ot Rerrd Englirh well:
\.orr read [rrglixh well arrttar* t]rteill in 
{nrutttt of tfu ltnguugtt}^ a lan$rtage
1lrattlrexutrject{hisilrerparetrt{s},.Iegor@well,Ycrrrtrndet.xtatrd1heC0iltet}f*ft}ris
corlse*t forur *,1cl y.l1 lave ir.anslrterl f"rx-the sulrject (his,.her parerltts.)/legal gunftliari) tlre eutire ccurteni
of tliis fo*,. T* tUe frest o1, y*tu li:ro*'ledge. the subjecr tlrxiher pareutts)ilegsl guardintt) ttrtderstatlrls
shlly, ald tlese rl"resligus Irill'e brcrr iluslvr:retl this,{rer puelttlti)'krg*l g[&rrlian)'
Reliler', Trattslitl or N ttttte
RtaderlTlartslatur Si grtatttl e
Datt'
Wituess Name:
\\'rtness Stgrtattue:
Date


E
Signnture of Investig*tor/[ndir,itluul Obtaining Consent :
To the best of ,votu'abilitl'. vou lrrve eriplaineel aud cliscusseel lhe tirll conlent* of the sfitdf iucludins all
r:f the inlonnstiou conlaiued ur this conreut tbnn. All queitiens of the t'esearclt sub.iect attrl fltose of
his:trer p*r"errt or bgll grulldirrrr lttr.'r" tl*r,:n scttrnlt"ll,*ttsrvrlred.
Iuverti gnti:r/Persol Obtauring {'oltse}tt :,
Siguature
I)ate.rTr:rre: