untitled h1
untitled h2

| 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   |
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| Date of the Document:                                                                                                                                                                                              |  
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).  
  
  
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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 l.  
2.  
3.  
,1.  
8.  
9.  
10.  
ll.  
| 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                                |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------|
| ' -.,.,.,.'..,.,.'...'-..'..,.,.,.,.,.,.'. ..' '.,.,.,.,.,.,.'.,..,.' ,.,.,.,.'.'.'.'.,.,.,.,.'..,.,.,.,.'.'.'.'.,.'...' ,.,.,ll                                                                                                                                                                                                                                                                                                                                                                                                                   |                                             |
| 4.5 DISLASE PROGRESSION CRITERIA DURING R.{NDO]\,IIZATION STAGE TREATMEN1 ,...,. {.6DURATIONOFFOLL()\V_UP I? 1? .S, I I)iCLLJSION CRITERIq 5.: EXCLUSIoI. I.RITER]A 5.-1 \\,'0MENANDNIL\ioR-TTIES 1-1 :,.I C.HILDREN ... I .i .5. 5 STLIDY Ei$,ot^I,MENT PROCEDLIRF-S. - t: ?.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? |                                             |
| 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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Pr.'tt,iul Vc:! .,(,1, S rr l l r ,l lr l - |  
Pr.'tt,iul Vc:! .,(,1, S rr l l r ,l lr l -  
I  
r2.  
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                                                                                                                                                                                                                                                                          |              |
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| 13.                                                                                                                                                                          | IJ.3DATASL:BM]SSIONTIMELtrIEA.}iDF0RMS,.,                                                                                                                                                                                                                                    | , :I         |
| l.i.,l REP'RTS                                                                                                                                                               |                                                                                                                                                                                                                                                                              |              |
| 14. 15.                                                                                                                                                                      | I.i.I IRB APPROVAI-S                                                                                                                                                                                                                                                         | ft           |
| I i,: OTHTR PRE-STUDY D0CI,:MEN]"IS                                                                                                                                          | 11                                                                                                                                                                                                                                                                           |              |
| 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                                                                                                                                                                                                                                                                           |              |
| 16.                                                                                                                                                                          | 1 6. i OL.rcoME lv-{EASLrRrs I6..i SAMPLE SIZE AND STATISTICAT. ANALySIS                                                                                                                                                                                                     | ..,.,.,:J ,! |
| 17.                                                                                                                                                                          | ?.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$) also knour as AKT Alarure transarnilase A\{P-actir,ated pr otein kfurase Aspirin Aspartale artrinolrausltrase Absohrte neutrophil corurt Androgeu rBceptor Blood urea rutrogetr Corrrplete blood cormt |              |  
Title: A Phnse 2 Randornized Disr'onriuunfion Trial il Patierrts u'ith Honnone-Depeldenr Ri;irrg Prostate-Specific Antigen Progressiou Aher Locnl Thelapr, lbr Prostate Cancer Etalrrating the S;*uerg1' of l\,{ertonrin Plus Aspirut
{PRI\IA Trial}. O"I  
| CINJ CTTTJOO CI cox C]T CTCAE CXR dL DNA DSNlP ECOG CCRF EGFR FDA GI IGT-I tRs IRB JAK LKBI S{APK iv{g nlL N{RI rUTOR NCI NF.KB Ng NIH OR OHRS OHRP PI.]K PI Pca PSA PSA DT Rb SAE SGOT SGPT STAT WBC   | '0rltldellce lrltell'a C'-vclooxl'getase Conrpuler Tonrogaphy Comnorr Tenrdnologry C'riteria for Adverse Events Clrest x-ray Deciliter Deoxylitromrc leic acid Data Sal'e6' hlomtoliug Plan Ea stem C'oopera tir;e Oncology Group Electlonic case reporl fomr Epider"nral lrowth thctor receptor Food and Drrrg Aclrnuristration Gastoiutestiual Irrsulin-like qrowth factor I lnsul iu relreptor sub$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   |
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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:  
  
  
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 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:
untitled h1
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.
untitled h1
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)
untitled h1
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 \.'
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\"{PK4epentierrt 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$as rece,tl,v repol"ted rg clu.ectlr, acrivate A|UPK ,"iir*it-v [65]. Dirr eI dl. recer]tl}' shorvecl that aspirirt aloue or courbiuatiou of aipiriu anrl rnetfonrrin ac:tivites A\,{PK and inhibits niToR sigrralirlg in Title: A phase I Rauclonrized Disconrirruation Trial il Patieuts u'ith Honuone-Dependerrt Ririlrg Prostate-specific A.,rige, progressio' Aher Local Therap.v for Prostate c'ancer Etalrratirrg the s,l'terg,l of N'lettbfl,il Plrrs Aspirur |PRII'IA Trial). i,t'I
colorectal cancer cells [66]. Potential il]echauiuus CIf synergistic actiorr of these trvo agettts in paucreatic cancer have treen re\''ie$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''  
  
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 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
untitled h1
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 Pr"otocol Versiort Versiol 8.00 IJl0lr?011 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. Participatinglnstitutionstreated 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.
untitled h1
{.1 disease assessment after run

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"
untitled h1
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
untitled h1
{.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.  
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
untitled h1
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-
untitled h1
5. patient selection criteril 5.

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 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 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
untitled h1
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 tlte investtgator.  
5.1.1 Patiertts mav have received prior ADT irl setlittg^ btrl uttrst t:e otf therapy fr:r at least the ueoailjrtr,attl. acllttvant auct''or salvage 3 urortths arttl ltave a tr'slosteror,,a lq1'el :'
-5.2.3 150 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.  
```
5.?..1
5.?.5
5 3.6
5.?.7
5.3.8
s.2.9
5.2.10
5.3 1I
5.2.12

```  
-5.2.l-j 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
untitled h1
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
untitled h1
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.
untitled h1
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'
untitled h1
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'
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  
| off                                                                                   |                                                           |     |    |    |
|---------------------------------------------------------------------------------------|-----------------------------------------------------------|-----|----|----|
| Treaturerrt (+30 days)                                                                | Follorv Up'                                               |     |    |    |
| Er,aluatiotts                                                                         | Pre-Shtdy                                                 | Ott |    |    |
| Treatrnent (er.ery.l weekri + j days)                                                 | Randomization Da1' 1 of 1" Ciycle Post 4 N,'Ionth Lead-In |     |    |    |
| 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  |    |    |
| \l                                                                                    | x                                                         | \.8 | \  | .\ |
| Proslale-specific anti gen (PSA) * l.                                                 | irreillr.ithirratr.eek,rfrtarrirrgClDl{thisPSA            |     |    |    |
| *'ill ertablish a baselile to asses$ retpogte and rrill ttot detenlrire eligibility)' |                                                           |     |    |    |  
```
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 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'
untitled h1
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'
untitled h1
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.
untitled h1
7.3 dose iliotlifications or esclstions

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.
untitled h1
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.
untitled h1
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 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'
untitled h1
7.6jldherence/(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' rvho calurot trlairttain this level 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' 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 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 E'Reporting Keporttng SAEs )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'  
  
  
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
untitled h1
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'
untitled h1
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 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 hrbes autl ti'ozett for batched analysis b-v ELISA'
o To monitor aspirin levels irt patients' salic,vlate levels evetl olltel cvcle.  
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
;r-1 ,"rvillbent'''
;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'
untitled h1
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 CiINJ phar:rrac1 vouriting. tlatttlence. aslheuia'  
  
Atlverse Reactions: \[ost corrunr:rn: diarrhea' lliluse'l' iucli gest ion. abriotttittal discorn lort artd headaclte' 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
untitled h1
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 '
untitled h1
13. dnt collection rntl llecortls

13.l ('rrse RePnrt FormsCRFs. 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.  
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'
untitled h1
13.{ reports

Publicatiorrs arrd nrulral reports for s1lrruissi6n tg the lRB Bnd FDA ivill be wrilteu by the iug the clata captrued on ttre eC'RFs.  
1.1. Drrtl and Safetr' \Ionitoring
-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''
i;:1ff,iiiii'1,;l'll,il'lil5r occru i, accorrlance witrr rhe
-
untitled h1
15. ltulti-instittttionrtl guidelines l5.l irb

Astlre(.trotc1ittalittg.(e,ttterioratrial.rti-'l,..H]ffi?ix1'!*l!"$:llx.',:ili:.:
patients are entcrerl tril llre trial at a petltctpatttts tltsllttttttr OHRS rvrll appr,,,r.e tire aclclitiou of each pairicipating instinrtrort tr-r the stndv. A copl'of the iRB
appror,al clocur,eul frour each participaiing institutr.rn rvill be obtainecl b-v the OHRS prior (t)
aciir,otion of the stircir,at tle ,articipati,g irrstittrtio,.  
15.2 Other Pre-Studl' I)ocuments Each participatillg cetiter is requilecl o ('tu'ricitla \.rlee of ail ph1'sicrart "
,to ltave the t-ollowirtg doctturents ol file at OHRS
Investigalors rysiciau lur;estigators (if applicalrle)
of all plt,vsiciart Ittvesltgators
. ectio, trai,i.g iorn tll l,r'estlgators r Sigleci 6restrgntor.ilgreenlent fronr the Principiil ltt"'esti$tator at eaclt participirling celiler r l{eclical ltcettse ftortt eaclt Investigator FDA foul 1572 of all
untitled h1
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'
untitled h1
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:
Patieuls lvith Horrnone-Depeudent Rising Prerstate-Specific Caucet Etalrratirrg tlre Syrerg.v of lr'lettburril Plrrs '{spulr Title: A Phase I Ratrtlotttrzed Discontiruratiol Trial in
.fuitigen Progressir:rr Alter Local Thelap-v lor Prostate PI
a crurellt contiruing appl'o\:al is ur:t ott iile at OHRS'
Rutgers tlniversity celitrfll IRB rvill nol be required to at ar)* participnting instittrtion ur rvhich C'entem tltat nre ltpplo\:ed to trtilize the file corttirtuittg ret'ter,,' docttntentatiol.
untitled h1
l5.5 tmendirrrnl lntl ('onsentr

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.
untitled h1
15.6 prtient registrltion

All pattents tlot)r pilrticipating urstitutiolls nttlst Regirrtration De:k. its clescribed in Section 5'7 of this
untitled h1
15.7 data ('ollection rnd toxicit.v

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.
untitled h1
15.9 drta 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*'
untitled h1
i 6. statistical consiclerations 16.1

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 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
untitled h1
16.2 outcome l'iesures

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"
untitled h1
16.3 sample size rntl stntistical

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'
untitled h1
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)
untitled h1
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)'
untitled h1
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.
untitled h1
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.
untitled h1
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 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.
untitled h1
17.6 gentler antl minorities

The Nntiouirl Instihttes of Health ancl NCI
iuchrsion in clitrical sel\'tces aud researclt 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.  
rliuical research lrials rvere 70o Ati'it:an-
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.
untitled h1
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.
untitled h1
19. publicltion of resenrclr findin

The policies attcl procedtrtes of clepat1rl ettt (see: Ilvesti[tator's Handbook)
i all e'o-attthols prior to ffiJnstitute's PI. arid rttarrtrscrtpt rvill govetr publication of the liial. The subinission ol' use^ unrst ret'iew arrl'abstracf t'lr Referertr-.es 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 I
l
-1.  
4 6 7.  
8.  
9.  
l0 1l l2 13.  
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' 343844.  
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' l ,l.  
Protr:col Verxiol 8.0 I:,'0lilOla 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.  
18. Lip B. Firu Z. Etlgerton Sl.t. Oeug XS. Aliruova IN, Lind SE. and Thor AD. l{e$bmin Itttlucc.s L\tique Biological and l.{olectrlar Resportses in Triple Negaliv*e Breast Ctncer Cel/s. ('ell Cy'cle. 2009. 8(13): p. 2031-40.  
19. .Ioshlir A\{. Ztrrutella VE. Downes NIR. Borves B. Helsey K. Kolitzinskv Ir{' Schrvatr lvf.  
Hgfltarut LI, Er:ans A- \,illr {er Kq,asl T. Trachtenberg "I. Filelli A. Fleslulel N, Sweet J. a[cl pollak 1t1..{ Pllor '[I'itrtlox,t{Opporrurih,'Neooriijilt{t,tt Sltdl'oJ'} etforttiltt irr Loculi ed Pro.strrtr, C'ttncet'. Prostate C'attcer Prostatic Dis. 2014. 37(10): p. 30' 20. Tariglc[iC'i\,{. Eurallelli B. arxl Kaln CR. C'rutical.$oder in Signalling Pallnvays lttsights irtto lttstrlhr -lctirtt. Nat Rev Mol C'ell Biol, ?006. 7(?): p. 85-96'
? l. N{atsls[ilie H, Qlelle DE. ShurtletT SA, Shibul''a M. Slrer"r' C'J- nnd Kato r}'. D-Type Ctclitt-Do7tctttlettt KittetseJr/ir.'in, ilt l,{mnm*linn Cells. N'tol Cell Biol, 199d. ta(3):p' 206676.  
??. N.lalilgu3pu-,ra R. Sacco A. Morcavallo A. Squalrito S. lvligliaccio A. lvlorrir:rre A"
Maggi..,l1u N,1. aucl Beltiore A,, A,.Ietforntilr Inlibits,4ndrogen-Ittdncecl lgf-lr up-Regrtlcrtion in Prosrrrtt, ('{ntct,t'Cell.s' b.t' Disnryring l{entltrone-Initittetl Arulrogert Sigrrn/rrrg' EndocLtttolcrg.v. 2lll{. 1-s5(4): p. 1207-2 l.  
?3. N,lills i;.f. \\rr P. .\lbertcur ]l.1. Kanters S. Lauas A. and Le$ter R. Low-Dose,4'spi|tn onrt Cttrtctt. ,\lot.ktlit.t'; ^1 l{eta-Artnlr'sls o/Rnrrdoti:ud Trial,v. Aul J N'{ed. 20f 2- l?5(6): p. -5607 24. Tlrrur \1.T. Henlel. S.I. and Patrouo C'.;\io,,sleroidal Anti-hyfitutltnototl' Drttg's os Artlicrrrtcet'
.{ger//.\ J{ecltrrrri.sti<', Phrtntt6calogic, rnul C'linicnl.Issire.s. .I Natl C'ancer inst- 2002. 9a(a):
P. l5l-{;6.  
:-i. Chan .\ I " .\rtrer \. IJurn .1. C'hia WK. Elrvoocl P. l'Iull lr'1A. Logan R]'. Rothrvell PLI. Sclur:r K, aucl IJa1r"1t JA".J.splrirr in tlrc Clwnopr€rvntion of Co{ttrectol Neafln,sitt: -4il Ot'ett'iesr:'
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untitled h1
appendix a

| 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.                                                                                                                                                                                       |