untitled h1
untitled h2

| Official Title:       | Phase l/llTrial of Letrozole (Femara) and Sorafenib (Nexavar) in Postmenopausal Women With HormoneReceptor Positive Locally Advanced or Metastatic Breast Cancer                                                                    |
|-----------------------|--------------------------------------------------------------------|
| NCT number:           | 00634534                                                           |
| Document Type:        | Study Protocol and StatisticalAnalysis Plan                        |
| Date of the Document: | 07lo8l2o14; SAP- page 4t 16.2 & p 42 L6.4; 02/1312013 .-.d f€- =l. |  
Title:  
PltaseliIITrialtlfLett<rzrrl"fanclSorat'et,i,,r  
  
*Role is non-clinical. no 157? r'eqrrired  
  
iii::I,,lIi]ii;jff,["i:::H:,txiiI*.m,:H:?:::I,ii:l,tj,,Poslllrertopattral ,,.I  
| TABLE OF CONTENTS                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                               |                       |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------|-----------------------|
| I.                                                                                                                                                                                                                                                                                                                                                                                                                 | PT'RPOSEISPfCIFI('OBJE('TT\]                                                  |                       |
| 1.I PRtrv{A,RY ENDPONT l : SEC0NDARY Exnponr:                                                                                                                                                                                                                                                                                                                                                                      | 5                                                                             |                       |
| BAC'KGROI.-\D .L\D StG\'I                                                                                                                                                                                                                                                                                                                                                                                          | : .5 .6 .7                                                                    |                       |
| l. I .,{ Brci-ock- lNo ntsc;Iltc conng                                                                                                                                                                                                                                                                                                                                                                             | l0 l0                                                                         |                       |
| a ,'                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                               |                       |
| t2. 2.I .-T RATIoNATE FoR STUDY 3. PARTI('IP,TTtI G INSTITT'TIO                                                                                                                                                                                                                                                                                                                                                    | I I                                                                           |                       |
| [\PERI}'IE:{T,I"L DESIG)i .lJ                                                                                                                                                                                                                                                                                                                                                                                      | t 2                                                                           |                       |
| 4. {                                                                                                                                                                                                                                                                                                                                                                                                               | P.TTIEIl' SELE( TION CRIT                                                     |                       |
| -5 5 5 5 5 5                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                               |                       |
| 6.                                                                                                                                                                                                                                                                                                                                                                                                                 | -1 I]'iCLuSr)N oF \\,oMEN AND T{NOR"ITIE                                      | l4                    |
| 4 PARTICPATIoN oF C:I{ILDREN                                                                                                                                                                                                                                                                                                                                                                                       | ,..14                                                                         |                       |
| -S S0URCES OR N,IETH0DS oF RE{,R 6 STl,iDY ENROU-\.IE},iT PRo(. EDURES                                                                                                                                                                                                                                                                                                                                             |                                                                               |                       |
| (i, 1 EFFICACY ASjSESSME}{TS                                                                                                                                                                                                                                                                                                                                                                                       | 16                                                                            |                       |
| '7.                                                                                                                                                                                                                                                                                                                                                                                                                | TREAT]\,TENT PL.{N                                                            | l6 t6 l6 16 l'" l8 t: |
| ?.6 CoNCoMrrAI.i-r \rlfDICATIoNS ? SUPpORTI!9'E CARE GUIDELINES,.,.,.,                                                                                                                                                                                                                                                                                                                                             | 22                                                                            |                       |
| ?.8 .{D}GRENCE C:oN{pI.tA:icE                                                                                                                                                                                                                                                                                                                                                                                      | _-1                                                                           |                       |
| 8.                                                                                                                                                                                                                                                                                                                                                                                                                 | TOXICITY MONITORI}$G A"\iD AD\TIRSE E\.'ENT REPORTI\G                         | 23                    |
| 8.1 DEFNruoNS Ar\D REpoRr"$ic REeLmEMEryrs oF AD\ERSE E\.ENTs.,REACfioNs                                                                                                                                                                                                                                                                                                                                           | .2.1                                                                          |                       |
| 9. TRE.dTIIE!{T fvAI.t-ATI0NiC:RITfRLt FOR RISPOX.SE                                                                                                                                                                                                                                                                                                                                                               | 28                                                                            |                       |
| 10.                                                                                                                                                                                                                                                                                                                                                                                                                | RIMOYAL OT PATITNTS FRO}' STTIDYIOFF STIIDY CRITERI{..                        | 12                    |
| rr.                                                                                                                                                                                                                                                                                                                                                                                                                | L,l"BoRdToRY f \r,{.Lf:ATIOSS A.]TD PROCID{.rRf Sr(:ORRELATT\,',I STL:DIES 32 |                       |
| ?. I GENERAL CONSIDERATIONS ?. 3 TREATMENT ADMNISTRATIoN,.,.,. .., .,.,.,., J.4 P}IASE I DOSE \-{oDrICATIoNs oR ESCAI.ATI0NS ?.,< PHASE II TOXICTTY A]\D DOSE M0DIFICATIONS .. I1.1 I 1.2 IMMLI,{OHISTO('HEMISTRY ANALl:sIS I l.l (.m.CULATING'I1;MoR (]Errs I 1.4 1 1.5 ll.,l OPTIONAL AND FLTTURE S1'TJD1ES (ON'I"Y FOR CANCER I),{STTN,."TE OF NE1U JERSEY PA,TTEMTSI . , 34 PHA.RMACETTTICAL I}{FORM.dTI0N -35 |                                                                               |                       |  
Phase I/II Trial of Letrozole and as First-Line Therapy in Postmenopausal Women with Hormone Receptor-Positive Locally Advanced or Metastatic Breast Cancer PI: A  
| 12.1                                                  | ..                                       |
|-------------------------------------------------------|------------------------------------------|
| 12.2                                                  | 38                                       |
| DATA COLLECTION AND RECORDS TO BE KEPT .              |                                          |
| 13.                                                   | 13.1 E LECTRONIC CASE R EPORT F ORMS .   |
| 13.2 R ESEARCH C HARTS .                              |                                          |
| 13.3 R EPORTS                                         |                                          |
| DATA AND SAFETY MONITORING                            |                                          |
| 14.                                                   |                                          |
| 15.                                                   | MULTI-INSTITUTIONAL GUIDELINES .         |
| 15.1 IRB Approvals .                                  |                                          |
| 15.2 OTHER PRE-STUDY DOCUMENTS                        |                                          |
| 15.3 I NITIATION S ITE V ISIT /M EETING               |                                          |
| 15.4 IRB C ONTINUING A PROVALS .                      |                                          |
| 15.5 AMENDMENTS AND CONSENTS .                        |                                          |
| 15.6 PATIENT REGISTRATION                             |                                          |
| 15.7 DATA COLLECTION AND TOXICITY REPORTING           |                                          |
| 15.8 DATA MONITORING AND SOURCE DOCUMENT VERIFICATION |                                          |
| 15.9 DATA AND CENTER AUDITS                           |                                          |
| STATISTICAL CONSIDERATIONS                            |                                          |
| 16.                                                   | 16.1 P RIMARY AND S ECONDARY H YPOTHESES |
| 16.2 SAMPLE SIZE JUSTIFICATION .                      |                                          |
| 16.3 OUTCOME MEASURES                                 |                                          |
| 16.4 ANALYSIS                                         |                                          |
| 17.                                                   | H HUMAN SUBJECTS                         |
| 17.1 SUBJECT POPULATION                               |                                          |
| 17.2 Potential Risks .                                |                                          |
| 17.3 CONSENT PROCEDURES                               |                                          |
| 17.4 P OTENTIAL B ENEFITS                             |                                          |
| 17.5 R ISK - B ENEFIT R ATIO .                        |                                          |
| 17.6 GENDER AND MINORITIES .                          |                                          |
| 18.                                                   | E CONOMIC/FINANCIAL CONSIDERATIONS .     |
| 19.                                                   | PUBLICATION OF RESEARCH FINDINGS         |
| REFERENCES .                                          |                                          |
| A APPENDIX A .                                        |                                          |
| APPENDIX B                                            |                                          |  
il,:::.1,'llili1"""*i:5H;:'ti.TII5.t#-I:;;l:?:::li::lfli,posil':re"opa"ia,  
  
  
PI:
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list of asbretiatioss

| .q,E ANC BLIN CBC CINJOC CT CR CRF CTC.{E DSIt{P ECG ECOC FDA HHS IRB Kg rnL urc$pg NCI ITIH OHRS OHRP PD PHi PI PR RW.IITH SAE SD SGOT SGPT LILN   | Adverse Event Absolute neutrophil count Bloorl ru'ea nitrogen Complete blood court Cancer Insfinrte of New Jeruey Oncology Gloup Courputer Tomography Complete respottse Case Report Forur Cotunon Tenuinoltigy Criteria for Adverse Evetrts Data Safery" Moniloring Plarr Elecnocardiopaul Eastem Cooperative Oncology Group Food urd Dnrg Athrrinistr"ation Depflflnlent of Health and Huual Sen ices hrstitutiorral Review Board Kiloglaurs Milliliterr Micropaurs National C-'ancer Lxtimte National hxtitrues of Health Office of Hurnan Research Services Office of Hrunan Research Protectiou Progressive disease Protected health infonnatiorr Principal Lrvestigator Partial response Rotren Woocl Jolursr:u University Hospital Serious adr:erse event Srable drsease Scrum glutaruic oxaloacetic fransarninase Serun glutarnic py,r"uvic u"arxarnina se Llpper liurit of nouual   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Phase I ll r'ial of Letrozole ,Il rntl sorafe,ibl u. Fi'rr-L ue Ther.apl.irr posr,rerropaural
\\totttett irillt Honttotre Receptor-po\nre Loclllr'.l,,hTirc letilit.lric Breest (nrrcer'
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l. purpose/specific olljectiyes 1.1 primary'endpoint

I.l.l Deteuuine tlte recorruuended phase II dose of soratbnib in cornbination with a tlxed darlv elose crf 2.5 rng of letl'ozole in palieuts rvilh homone receptor-positive locally advanced r:r ruetastatic breast carlcer.  
1.1.2 Detentrine the clinrcal beuefit rate {proportiou of patients rvho achieve a cc,trplete response. parlial respouse, rJr stable disease ), 6 months) of letrozole and sorateuilr in the first-lirre trefftrneilt of postrueilopalnal patients with hot'mone receptor-positive locally advanced or uretastalic breasl cancet'.
untitled h1
1.2 secontlary endpoints

1.2.1 Detennine time to progression and overall sruvival of patieuts treated rvith this combinatiou.  
l.?.? Assess the safbty and tolerat:ility of this corubinatiur.  
1.2.2 Evaluate courponents in the Ras-Rai'-lv{APK aud vascular endothelial srowtl}
thctor (\rEGn pathrvays in rrunor samples befr:re and atler treatruent (if available) rvith letrozole arrd sorafenitr.  
1.3.3 Evaltmte tlte cltartge in circulatins hnuor cells in peripheml lrlood before and aftel tlealmeut rvith letrozole and sorat'enitr.
untitled h1
2. background nnd signilicance 2.1

iu 2007. over 178.480 rvomeu rvill be diaguosecl *'ith invasir.e breast cancer aud 40,460 woulen will die of this clisea.se.lAlthough the last rwo (leca{les have wihressed significant advances in systeuric therapies^ metastatic breast calcer still reruaius ati illcurable disease.  
Once ntetastases are cliscovered. uledian su'v'ival lor all patients is only trvo to tluee -years.  
Given the lack of cruable treatulent. the urajor goals of therapy incltrde palliation of struplotns. tuainteuance of tprality of lit'e. aud inrproveurent in overall aucl proeression-fi'ee sun'ival. \\{rel choosing the optirrral therapy tbr rnetastatic breast caucer, one must take into account a nurnber of iactors. such as the likelihood of respoilse with a par"ticular therapy. its side etl'ect protile, and ease of adurini.stratiou. hr addition. consideration of an individual ttun.ol's biologl, all:rvs the tailoring of therapl,to optirnize resources and 0utc0rnes.  
Honnoual therapy. such as selective estrogen receptol moclulatr.:rs. aromatase inhibitors.  
aud estrogen antagonists. is a urajor treatrrlerlt optioll for r,vomen ryith houncure recepfor-positive uretastatic breast caucer'. Approximately 759.o of breast caucers are positive lbr the eslrogen receptor (ER). the progesteroue receptor (PR). or both.l Atrout 50 to 600ro of patierrts rvith hortroue receptor-positive nunors respr:nd to honnonal therapy.  
Approximately 20 to 35qt r:f patients with honnone receptor-positive metastatic breast cancer will experierce an olrjecti'i,e l'espon$e to initial lu:nuone therapy. Horvever. a portioll of homrone receptor-positive patients rvill ur:t respond.  
Phase I{I Trial of Lekozol.f anct Sorafenibl a; First-Lile Therapy in postrmroparxal
\\'ottrett n'ith Horrrroue Receptor--TJjiive Locrlly ,+Ar?iiElFfi'teralraric Breast Cancer
-
I)ala aIe evolviltc iu preclinical urodel$ denronstrating that estrogen modulates artgiogenesis. iu part tluough effects on VEGF.3-6 Doto also suggest ttrai estrogen (E2)
utodulates \''EGF-incluced angiogeuesis iil physiologic and pathologic ci:rrt{itions. One study irt an androgen-dependeut nmle tuorrse rnodel of breast carcer clenroustrated that castlatioll restrlting in the reuroval of aildroeer) catnes nutlor regressiou. There rvas also a rcdttclit"ltt itt ltttuor vascttlafure irt lesptlnse to caslrafitln aud androgen cleprivation thal cotrelated rvith a clecrense in VEGF at the ruolecular level. particularly 7 days after castratiou.T
Theretbre. orle wa,v to eultartce eudr:crine sensitir,ity aurl delay disease progression iu patients rvith ltorruoue receptol'positive urelastatic breast callcer is lo acld al anli-VEGF
therapy. such as an oral tJrosine kiuase irrhibitor of VEGF, to stanclard anti-honuonal treaturettt lbr patieuts rvith lrreast caucer. In thi.s trial, rve will test the hypothesis that adtiing au anti-angiogeuic agent rnight clelay' the onse{ of resistauce to eadocrine therapy.  
specitically estroseu deprivation rvith an aromatase ithibitor.
untitled h1
2.i.1 aromatase inhibitors in postmenopausal

Aronratase irrhibitors (AIs) block the cfocluome P450 erzvule aronratase (C'YPI9),
thereby prer,.entiug tlte conversion of andlostendio[e to e$trone aud testosterone to estradiol. Lorver estrogeu levels deprive the turnor of its gror.vth stiruulus. This pl'opefi)
ruakes AIs iu parliclilal suitable for postureroparxal woluerl rvhose main soruce of aclive estr'ogeu is the result of peripheral aromiltization of arrthoserl precrusors.  
The tlrst-generatir:n compoturt{s. such as aruinoglutethirnide. \vere associated rvith siptificant toxicity Subsequeutl.v. second ald third-generatiou comporurcls have been developecl artd irtclutle anasn*r:zole. letrozole. and exernestarre. -I'hese agenls have shown exquisite speciticity and are higlll), selective ilr targeting the aroruatase enzyrue. Second-generation AIs are either steroiclal or nonsteroidal. The nonsteroidal cornpoturds (i.e.,
letrozole- anastrozole) couipetitively ifl1151t the arouratase enz\,ne rvhile the steroidal compounds. such as exemestane. inerrersilrl1, irractivate the enzFne.  
ln the last tlw years. AIs have shorvn tr: be equivalent or superior^ il efficacy to tarnoxifen
(and also of siruilar or better tolerabilitrr) in the tirst-liue treahuent of po-stureuoJrausal wotrtel] rvith lrounone receptor-positive advarced breast carcer as rve[ as in the adjuvant setting.sll
untitled h1
2.1.2

2.l.2.ffirents:I*(J.J'-1lH.l.].{.triazr:1-l.tinretlrferre)[:is-benzouitrile) is a srerthetic aclural Lrerzvclnl-triazole ilerivatir.e. It is an orallr,.active highly selective nonsteroidal couq:etitive inhilritor of the ar"omatase elu\,l1]e $].stem.11 Letlozole el}'ectively in}ibits the couversiou of anclrogels to estrogens in vitro and in vivo. Letrozole is up to 150 to 250 tirues more potert than the first-geueration AI. arninoglutethiuride. in vitro and rnore thau 10.000 tirues as poteut as aruinoglutethiuiit'le iu inhibiting arouratase irr t,ivo.l-t Ttre high potencv qrf letrozole is not accorirpaniecl by any significant eftect on adrenal ,steroiclogeuesis in vitlo or in vivo over its rnaxiurally effective d,:se range.l]"!3  
iiffi lilliJii;iff :"i:::m*'lffi,n.,l ;l: tr.I1:',1l,;i"  
  
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Thus. it is also a highlv selective iuhibitor oi arouratasr'. The higrh pr:tency and selectiviry of letrozole explails its favorable phar:nacological protile and high therapeutic index. Ll poshnettopausal patients rvith adr,aucecl breast cancer. claily d6ggs of 0.1 to 5 rng leh'ozole suppressed plasua ler,els ol estractiol. estroue arrd estrone sullhte by 7-5-950,ir ti'our traseline. I {
2.1.2.2 Clinical Information: A Phase III gk:tral. multicenfer. r'andonized clinical trial evnltmted letrozole (2.5 rrrgklay) as a first-liue homronal therapy as cornpared to the preseut starrdard of treatruerrt tauoxifeu (20 ruglcla.v1.s This trial accruetl 907 poslruenr:pausal womel) r','itlt ER an<tior PR positive or uuknowr) receptor trreast cailcer aud locally aclvauced disease. uretastatrc dixease, or loctr-regiouill recruleuce uot rurenable to treatruent b1, stuger,v or raelir:tltelapy. Patients receivecl treatment until clisea.se progressiou or discontintmtion tor ary other reason. The priurary errdpoint was time to progression (TTP).  
Letrnzole rvas superior to tauroxifen and reduced the risk of progression by 28o.,b (hazard ratir: 0.72. P < .0001). Tlre rnediatr TTP rvas prolouged by 57o,b: 6.0 nronths tor tauroxitbn vs. 9.4 ruoutlts tbr letr^ozole. f'he seconrl*ry euclpoiuls irrcluded overrll tumor response rflte.  
clinical benetit. artd tirne to treaturent thilure. Or.erall trunor' ,espon$e rate (cornplete and partial response) rvas sipnrificantly higher rvith letrozole (320..'o r,s. 2lo;b. P = .0002).  
inespectir,e of doruiuaut site ol clisease. Clurical benetit (courplete respollse. partial respoose or stabilizatiol of disease) lastirrg at least 3$ r.veeks rvas 500.''o for letrozole vs. -1896 for tanroxil'en (P = .000.1). fiure 1o treatrnerll faihu'e was siEriticaltly better llrr letlozole ct'nupared to tanroxitbn (9.0 rnonths vs. -5.7 months respectively, P =.0001.) The ureclian overall sruvival was slightlv prolotged frrr letrozole r.s. famosit'en (34 rnonths rrs. -30 uronths. respecti\relv). This ditl'erence is not sipnrificalt. However- the studv desipar incltrcled a classoyer to the other treatr:lent arlll at the discretion of the iuvestigator. fui aualysis rvas doue irr the patierrts lvho did uot cl'ossor.er. rvhich deurousfialed a lS-uronllr srurrival advarttage iu the letrozole treatrnelrt gro,qr.'-'The clata cutotTfcrr this aualysis rvas Septeuttrer 1001 r.vheu mecli*n tbllorv-up rvas 33 months rvith a uraxirntuu obsen'atiou period of 57 uronths. Tolerability r'vas similar in both ar:ns of the trial, rvith 2% of patieuts on lett'ozole aud 3o.ir of patients ou tanroxifen discoltiuuing tlrerapy due to adverse events.  
2.f.2.3 Summar\': Letrozole has a highlv favorable toxicit-v protile ancl is superior to tatuoxif'en m tenus of TTP aud courplete respouse in patients with locall-v advanced and utetastatic breast carlcer'. Based on this snrd-v and other suppor-tive data. the FDA apprerved letrozole for flrst-line honnonal lherapy in locally advauced or rnetastatic brea.st caucer in Jaurmry, 3001.  
2.rJ-2.1.3.1 General Comments: The Ras-Raf-N{itogen activatecl protein kinase (IUAPK)
pathwaf is a critit'al sigraling pathrvay iuvolvecl in cell proliferatiorr.'u hr"r"ored activatiorr and overexpression of Ir,{APK have treel obsen.ed in breast tuurors-l7 N{oreover, a sipnificaut positive associatir:u has l"reen shorvu lrenveeu activatetl I\'LI'PK ancl the presellce of lyuph uocle ruetastases.ls There also aJ:1:ears to be sigrrrticant cross-talk benveen the IIA.PK ancl ER pathrvavs. rvith actirration of N,IAPK resulting in ER phosphorylation and activnliort in a sleroid-independent rnauner-le Lr fact. eudocrine-resistnnt ER-positive lx'east  
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iii,tilsil[.11ii,1""fl ::Ht.:'l;'xi:t]'if ilt]:il:?::^I'r'J,,1,;J"pos.':re':ro,a"ia,
caucer cells strorv iucreased depeudence r:n trilAPK-uredialed sigualiug. hrhibrtiou of the  
  
critical Ras-Raf-lvLA.PK pathrvay thus is Rn attraclive potential freatrilent ftrr breast caucer.  
Sorafeni[: (.1- i'1-[-]-(.4-chloro-3-tritltrorornethyl-phell,l)ureiclo]lherroxy] -pyidine-2 carboxvlic acid utethylaruide-,tr-rneth,vlbenzeusultbuate), a bi-ar,vl rrea. is a potent inhil:itor ol'rvild-lq:e ancl ruutant b-Rafkiuase isoftrnns iu vitl'o. It also ilrhibits the lyrosine kinase of VEGFR-I. VEGFR*2. VEGFR-3. PDGFR. anti c-KIT.'o By inhibitirrg Raf. which iltteracts at the plasrna uterntrrane rvith activated Ras aucl initiates the h{APK cnscade. this clnrg suppresses tlte siplraling events required for huuor proliferatiol. Sorafenib is crurentll' approved for the treatrireut olpatierrts wth aclvanced renal cell calcinonra.2l Angiogenesis has treen shown to be essential to the uoryth of solid nunors.ll Vascular endothelial grorvth tnctor (\'EGF) is the dourinaut 5uowth factor controlling angiogenesis.  
Levels rtf VECiF are urarkedll' elevatecl irr the vast umjorit.v of trunors and vascular prorvtlr aud l'onnatiotl are ket'courpoueuts iu prouotiug aud srxtainiug hrmor sunital. In breast czu'cinoura. trunol angioeenesis has been reporled to have propnrostic sigurificance.2l Specificall-v. a statistically sipriticaut comelation lretrveen uicrovessel density and lylrph node status as rvell as iucideuce of rnetastases has been clerrronstrated in patients with lrreast
..rl""r.l* By targetiue the \"EGF receptor. sorafbnib also iuhibits nunol' augiogeuesis anil deprives lhe htntor of the neovasculalization lequired to sustain its grorvth. Sorafenib is theretbre au attractive tlterapeutic agent giverr its potenlial to preverrt tuulor grorvth by irrhibiting both tuuror cell prolileration and hunor angiouenesis.  
2.1.3.2 Cllinical Information: The salbty ancl clinical activitl' of sorafenib. alone or iu combinatton rvilh chemotherapy. has Lreen examined in a series of phase I studies coudttclecl iu palieuts rvith solicl tu[rors.]t l0 hr a rrrulti-cerrler. randourized. placebo-controlled. double-lrlild phase III trial of 906 patients q,ith aclvaucecl reual cell carcinorna
(RCC) rvho lncl received one prior svsteuric therap-v. soral'enitr-treated patierrts had a rnedian PFS af 24 rveeks versus ll rveeks for the placebo €x'eup (hazard ratio 0.4.11 p.i0.00001).:lJI The ll-lveek proglessiou-ti'ee rflte was 79o,b tbr sorafeuib versus -50o,'o for placebo. Based on these results. in N.Ia-r" 2005 the study rvas rurbliucled ancl patieuts iu the placebo $oup allorvecl to cross over ancl receive sr:rafenib. At the tirne of ctoss over. arl interiut aual-vsis of r:verall suvival was conducted based on 220 events. l,{ecliau overall sutvival in the placebo group was 1.1.7 urorrths attd had nr:t beeu reached in the -sorateuib group. The hazald ra(io (sorafeuib over placetro) rvas 0.7? r.vith a p-vahre of 0.018. The tlu^esluild fbr statistical sigrriticauce lbr this interiru aual-vsis was uot reached (p .,: 0.0005).  
Final anal,vsis of OS rvas reported at the American Sociery of C'linical Oucology (ASC'O)
.{rurual Session ur 200?.ll Overall srur.'ival rn the soratbtitr group rvas 17.8 mouths and 15.?  
montlx in the placebo Foup (HR 0.88. p:0.t'16). For this stud.v, hor.vever. OS was likell''
conforutded b1' lhe fact that approxiruately half of the placebo patients crossed over at the tirue of urrblindirrg to receirre sorat'enilr. To illus{rate that poiul. overall survival aualysis rvith placebo patients censorecl at the tiure of cross over inclicated that scrrafenib treared patierts had a statistically,' sigrrificant 229[, reducti,rn in ruortality risk comparccl to placet:o patieuts (OS 17.8 Ine vs 14.-1 rno. HR 0.78. p:0.287). Based in part on these tindiugs, the iJ,',:;:l,i'Ii]i1"''.*i:l:-HJ:Ymn::i:?::."}[:iH,,Postrtrerlopattral
-
US FDA approved sorafbrrib tbr^ lhe treatnrent of patients rvith advanced renal cell c'alciuorua in Decernber ?005, A multi-center. rattdoruized. placelro-coutrolled, double-blind phase III trial rvas also condtrcted lbr parieuts rvith advauced hepatoc'ellular carcinoma (HCC) and rvas repored at
;\SCO in 3007.-]'r hr this stucly 602 paiieuts rvith aclvanced HCC'. Child Pugh class A.  
having not receivecl prior systeuric tlrerapy rvere raodornized to receive either sorafeuib
(n=299) at -X00 nig bid or placebo (n=303). In Febnrar-v 2007, trased on a plarureti interim artalysis of overall sunival. the data safety rnonitoring board recorurnended turblinding and closure of the sttrdy. OS in the sorateuib goup rvas 46.3 rvks verstm 34.4 rrr,'ks in the plar-:ebo-trealed group. This represeuled a -{4% increase in relative OS {FIR 0.69.  
p=0.00058). PFS rvas also sigrilicarrtly iucreased in tlie sorai'euilr gloup (34 lvks) vs the placebo Sroup (12.3 wks): HR 0.5S, p:0.000007.  
Sorateuil'r as a single ageut ltas beeu errahuted in patierts rvith urelastatic breast caucel in the plrase II setting. hr one phase II tl'ial" 5.1 patients r,vere trealed ivith sorat'enitr 400 mg trvice claily in 4-rveek cl,cles until toxicity. tiisea,se progu'ession. or cleath.l3 Alt patients hacl receir,ed at lea.st one prior clteurotherapy regirueu and hacl proElressed ou adjuvant honnoue therapy (if honnone receptor-positive) or trashlzuurab (if HER2 positive). The median h'eaturettt dumtion was 58 days (range l-40:). Analysis of the rtudy's priurarl'eudpoilt of trest respouse. accolding to World Health Orgauization cdter-ia. r.evenled a partial re$pon$e in one patierrt (20.o). TrvertfV (370.i,) wolnen hacl ttable disease. inclurling 22q'o and 119'o of patieuts disease stabilitzatiou tblrl uronths and 6 ntorrths" respectivell,. Sora{'enib rvas well-tolerated rvitlt one grade -t ctnrg-related adverse event which rvas all increase il GGT. The l]Iost coulmon side effects rvere lash,it{estluauratiou. auorexia. atrd hauctlfoot skiu reactious. 'hese toxicities rvere uilld-to-moderate and ciinicalll.'ruarmgreable. Anolher phase II study prirnarily coucittcted in the L\rited States euolled patients with metastatic breast caucer who tvere eaudidates tbr tirst or second-line cheniotherapy and hacl previousl,v leceiveti an autluacvcliue andior a taxaue in the neoadiuvart. a{uvant. or nretastatic setting.i{ Patients rvere lreatetl with sorafeuib 400 urg tr.vice daill,ou da1,s l-28 ol'each 4-rveek c_vcle. In this studv. 20 pts rvere elisible tbr etlcacv auallsis. One pt (5e'o: 959'i, CI 0.5-20.59,ir) nchieved a PR rvith chuatiou of .3.6 mr:nths aud one pfltient achier.ecl stable disease fr-rr at least 6 utontlts. Tlte 6-nir:nth orerall sruvival rate was 8lo,'o aud the progression-tlee suvival rates were 53o.o at 2 ntonths, 2,4o'b at 4 months and 6o.,ir at 6 months. N.'{edian tiure to proeression rvas 2 nronths.  
2.1.3.3 Summary: Although studies deuronstrnte limited activitv of sorafeuib as a single-agent in heavilS'pre-treated uretastafic lrreast cancer populatious, there is poteutial for efficacy in corntrining soral'enib rvith other agents. suc:h as chemotherap,v, honlone therapy artd otlter targetetl <tugs. There are several ongoing trials treiug conducted with soral'enitr irt ptrtieuts rvith rnetastatic Lrreasf cailcer. 'fhis includes a phase II trial of soratbuib arrd anastrozole in previously trca(ed patients rvith homrone receptor-positive disease- a randourized phase II tlial of J:aclitaxel with or r.vithout soratbaib ns first-line therapy in locally recun'ert or ruetastatrc breast caucer. aud a double-blincl, randomized
*-"'''1,'ii*1,f,["i:'.-:tt;::lffi,ni;::?::I'ff fl i"Postr,e*opa'lriar phase II trial of somfenih versll{i placetro in cornt:iuation rvith cheurotherapy after  
  
proguession on ber,acizuurab.
untitled h1
2.1.{ biologic antl imnging correlntes

Siuce sorafenib is a poterrt c-Raf and B-Raf kinase inhibitor and inhibitor of VEGFR-I,
VEGFR-3. VEGFR-3. PDGFR. and c-KIT tyrosine kiuases. coulponetlts of the Ras-Raf-I\LA.PK and angiogenesis patlnvays ruvill tre evaluated in hunol speciurens of patients eru'olled ou shtdy if available. We prcpo$e to measrre tissue expression of uito$en-acttvated proteiu kinase (h{APK). p}rosphorylated-}r{APH. \,,EGFR-?. and phosphorylated
\EGR-3. Effect on nunor prolifelation ivill be rueasu'ed by assessing Ki67 iu truuar samples.  
The clevelopurent of rrer*' fiearnrer]ts tor cancer could be thcilitated if tuuior cells could be sanpled directll' at utultiple time poirrts lirllorving the atlministration of a new dmg or dnrg cotubination. It is verv desiratrle fo have direct access to relevant target cells to learu abouf a dnrg's et'fect. Although rve rvill ln' to cl'recll1, saurple solid tuuror trlasses arrd evahmte the encl points described above. this rvill be dilficult. hr this rial. rve r.vill collect peripheral blttod for circulating trtmot' cells betbre treahuellt and atier trvo c,vcles of treatruent. In 2004. it rvas shorvn that fhe use r:f circulating huuor cells (CTCs) ftrr the uranagerueut of ulelastatic breast cancer patients undergoiuq s)rsteulic tlrerapy lvas a strong independerrt preclic tor o f pro gressiou-free s urviva I ilrrd or.eral I srurival. I 5 Dluaruic contrast enltanced maguetic resonance iruagin.e (DCE-MRI) has [:een used extensivel-v rvith novel anti-angiogenic ageuts in cliuical studies to urouitor their effect ou nullor vasculatule tluough paraureters reflecting both tumor pertirsion and penueability.  
Otlter tuodalities such as pertirsiou C:f (pCI) ruay seffe as a utxriuvasive tool to uronitor tlunor l'e.$pouse to therapy vin quantificatiou of trlood t'low pararneters. Perfrrsion CT
tecluriques have demr:nstlated decreasing etiects of different augiogeuesis inhibrtors on tumor bloocl florv parameters.-16-r8 hr thls trial, patierxs rurderg,Jin! iruagirrg stuclies at Robert Wood Joluror Unir.ersity Hcspital rvill have a perfixion CT perfonuetl [refore nealrnent and after tlvo cYcles of treatnrenf to assess luftror perttsion.  
C'orrelation berr"*een serial C'TC values and blood flr:rrv nreasurenlents frorn selial perfusion CT rvill tre perfomred as an exploratorv analr'.sis.
untitled h1
2.1.5 rrtionale for sturlv

Metastatic trrcast cancer is tnt cru'able. Horvever. in patients rvith homrone receptor-positive disease. qrmlitl'of life and druatiou of remission are inrpo(aut pararueters of tlreir treatuent. Dtte tcr its relatively lor,v toxicitv. homronal therapy is usually the tirst liue therap-v fbr rvotneu for initial reclureuce or low bruden of metastatrc disease.  
Therapy directed at artgiogerresis aud ftunor proliferation pathrval's in acldition to arornatase represents a potentialll'- nr:vel approach. We hypothesize that sorafenib, a potent inhrbitor r:f aueiogenesis as rvell as the IUAPK sigrralirrg pathr.vay. corrlcl ililribit the sipuraling events requir"ed lbt htntor prolit-eration rvhile letrozole inhibits ar'olnatase activif-y-.  
It is not expected that there will be a pharlracokinetic interaetiou ibr this combiualion trecause neither dnrg inhitiits or iuduces the ruetabolic pnthrvny of the other nt clinical concetttratiotts. There is also detailed phanuac,r:kinetic data available for troth dnrgs. For tltese reasotls. \\'e nill not pertomr detailed phamracokinetics as palt of the trial. hor.vever, tltis nial rvill include a sltr,rrt phase I coupouent r,vitlr dosirrg outlined ilr secliorr 7"4.  
\Ye chose letrozole as otu' AI because it is the only Ai to date to shsr$, superiority to tamoxifen in the first-line treaturent of metastatic postrueur:pausal breast cancer. alttrough thete has been no head-to-lread courpar:ison of a nonsteroidal AI to a steroidal AI iu the trealmettt setting, \\re chose a uonsteroidal intribitor trecause it has uo androgenic properties. unlike exentestane. a steroidal agent. rvhich has soure lveak androgenic side el't'ects. such as rveight gaiu. acne. ancl hypert'ichosis. hr tenus of suppression of estroqen and its rnetabolites, letrozole appears to inlpprcss plasura estradiol, estrone ald estrone sultate levels to a Eeaterextent than exeurestane (90.1 * 97.6oib vs. 72.9 - 89rq,o). althoug.h this was not delemdrred in a coruparative study'."'e'{0 ln additiorr. itt alornatase-explessing cellular ruodels. ilcluding lnuuan lrreast fibrotrlasts.  
&{CF-7Ca cancer cells and .IEG-3 hrurmn choriocarcilonra cell lines, letrozole has lreen contpat'ed lvith other AIs. suclt as allnstl'ozole ald fonuestane. a ster'oidal AI. ancl shorvn to be cormisteutlv more potent.a0 furolher stucll, lhal exaruineti the activitl, of arr:ruatase iu placerrtal microsomes ancl uranuuar-l tibroblast culfiu'es u,ith letrozole, anastrozole. or exemestane shorved that tbr each tissue. le(rozole had the lor.vest ICso and the highest poteucy. r.vhich suggests that it has the best capabitity' of ruhibiting aroruatase iu vitro.\#
Fru'thenuore. letrozole has also [:eeu shor,vu to exhibit tlre lowest residual aroutfltase activity al l.lqt verslr"s auaslrozole at 3.3{,'b and exeureslarre al:.I9'o.le'al Although the clinical t'elevance of these diftbreuces neecls to tre fiuther invesfigated. these strrdies provide fiuther srlppon tbr usiug letrczole as the AI of choice tbr oru shrd,v.  
We propose ustttg the corubinatiou of letrozole aud sorat'enib as first-line therapy iu postrneuopatxal ltorutoue receptorpositive patietts with locally advauced or uletflstalic trrcas( carce[^ We posftrlate that depriving honnone-depenclent breast caucer cells of estrngen in addition to iutert'ering rvith the nunor's proliteratiou sigurals and vascular snpply will be arr et-fective strategy in tlie treatureut of advauced trreast callcer aud uray result in ilIore activitv than r.vhat has beeu reporleel rvith letrozole as a single agent-
untitled h1
.1. experimrntnl design snd [ethotls

This is an open-label phase UtrI trial to cletemrirre the clinical benefit rate of courbinirrg letrozr:le and somfenitl it postruettopausal wJmerr rvith prcvior$ly s111r*nted honnote receptor-positive locally advanced or nretastatic breast caucer.  
Patiertts rvill receive oral letrozole once daily at 2.5 rrrg;day iu courbination with oral sorafenib at a daily dose to t.re detenrrined traserl upon the plrase of shrd-v that patieut is emolled.  
Lefirtzole aud sorafenib rvill tre talien c'ontinnously on Da-vs 1 tluouprh 2S (a cycle). The phase II dose of sorafenib will be detenrined fioru lhe phase I portiou of the sftrdy. Treatureut will be administered rurtil disease ptogtessiou or witlrdrarval from shrdy due to unacceptable toxicity or other reasous (i.e.. con$enl r.vitlrrlrawal, rlolt-compliance. etc.).
untitled h1
5" prfient selection criteril 5.1

A patient is eligible for rnrollment if all of the follon ing inclusion criteria sre met. 5.l.l Histologically confurned invasive bleast caucer 5.1.? Stage IIIB. IIIC rvith T4 lesion or Stage I\r disease 5. 1.3 ER-positive and'or PR-p,:sitive of prinrary or seconclary hunor tissue
-5.1.4 Wouren are > l8 years 5.1.5 Posnueuopausal stahts det-rned by one r:f the lbllolving criteria:
o Age .s6 or older and history of at least 12 moulhs r.vithout spontaileot$
rnenstnul bleeding prior to stud-v ently. or r Age -5-i or yoturger rvith a historl of at least l2 rnonths without rr enstnral bleeding. rvhether spontaleous or fi'oru a pdol hysterectorny, r.vith a clocuutented estradiol level withiu the instifutionnlr'laboratory postDrenclpausal mnge. or r R'ior docruuented bilnteral oophorectolny or o Ovariau suppressiorr by a luteiuizing honnone-releasing honncue
(L,HRH) agonist. N{edical ovariau supprcssiou car be initiated any tiure prior to or at the start of pro(ocol therapy. and conlinued tlur:ughout the chuatiou of the trial.  
5.1.6 Patierts rnust ltave an EC'OG perti:rurauce stahrs 0- l. or 2 (Appendix A).  
5.1.7 Patients mtnt have nomral nrgan and ulanorv fiurctiou as defined below":
. ANC coturt ) 1?00lpl,
. Platelets:" l$Q,SQff rpf
. Total bilinrbin < 1.5 X institutional ULN
. AST(SGOT)/ALT(SGPT) s ?.5 X institutioual LrLN, (s 5 X ULN if livel metastases present)
. Creatinille '':; 1.5 X instihrtional ULN
5.1.8 Patients can ltave Dou-ureasrlratrle disease or rleasmable disease according to REC'IST (Sectir:n 9).  
5. l. l0 Life expectarcy of 3 months or longer
\\,'onsi 5. l.l I Able to swallorv and rekin oral uredicatiou  
  
  
5.1.12 Writteu inforruecl consent
untitled h1
5.2 exclurion criteria a patient

5.2.1 Prior honrtonal therapv lbr uretastatic disease (prior adjuvalt tantr:xifen or arouratase inhilritor will be allorvecl)
5.3.? Pdor chenrotherapy tbr ruetastatic disease 5.2.3 Prior treaturent rvith sorateuib
-5.2.4 Patierrts with a histtrry of brain uetaslases or leptourerdrrgeal nretastases" 5.?.5 Second primar;* uraligrnncy except urost situ carciuorua (e.g. in sihr calcirrorua of the cervix, adequately treated non-melftnolnatous carcinorna of the skin) or other rnaliprrancy treated at least 5 years previously with no evidence r>f reclllTeltce
-i.?.6 Cardiac clisease: Conseslive heart faihue :' class Ii NY-I{A (see Apperrdix B).  
Patienls rrrust not have uustable angina (arrgirral sSrnptoms at rest) or nel onset artgiua (began within the last 3 months) r"rr turstable coronmy artery clisease r.vithiu the past 6 uronths
-5.2.7 Seriotrs couconritant systernic disorders (includilrg syrrqrforuatic congestive lreart tailure. turstable angina pectoris. cardiac an{rylurria requiring therapy.  
rnyocaldial iutarctiou ivithin the past 6 months. or aclive iui'ectious or se\:ele hepalic iurpainnent) that rvr:trld c,rmprourise the safety of the patient or compromise the patient's abilitl. to complete the study. at fhe discretiou of the investigatot 5.?.8 Uucontrolled hlpertension defured as sy'stolic blood pressu'e r:' 150 mur Hg or diastolic pressure r.. 100 rruu Hg. despite optiural niedical mailagement 5.2.9 Histr:r1 of allergic reacfir:rrs attritruted to compoturds of siorilar chemical or biologic corrrposition to letrozole or sorat'enib
-5.2.10 Historl of allergic t^eaction to sulfonaurides 5.2.11 Tluourbolic or euLrolic er,'ents such as a cerebrovasc,ulal accident includins trausient ischeuiic attacks within the past 6 ruonths 5.2.l? Serious non-healing rvormd. rilcer. or boue tiactrue 5.2. l3 Evideuce or hisiory of bleeding diathesis
-i.2.14 lvfajor slu'gel'). oper biopsy or xigril-rcnnt tralunatic irrjur-v rvithin 4 rveeks of first shrdy drlg 5.2.15 Use of cl.tocluoure P450 enzyure iuducirrg nntiepileptic dnrgs (phenyoirr, carbamazepine. or phenobarbital). or St. Jolur's Wod t-rr ritarupin (ritarupicin)
5.2. I 6 History oimalabsorption s,urdrorue 5.2.17 Patients rvitlt itrunune deticiency are at increased lisk of lethal inlections rvheu treated rvith rnarrow-suppressive therapy. therefbre. krorvu HIV-positive patierts receirriug conrbination anti-retroviral therap;* are exchrded fiom the stud-v because of possible pharruacokinetic interactions r.vith soraferrib.  
Phase HI Trial oi
\\'otrleut.ithHorrrrolIet:.::.,.etffiitaticBfea'tCattcer
untitled h1
5.3 inclusion of vomen and

Wornen florn all racial,letluric Erroups are eligitile fbr this study if tlrey ureet the eligibility criteria" Ir,{ales will rmt tre eligible for this sftrcl-v. Breast cancer it ureu is rare and the etlicacy of aromatase iuhibrfors iu urales is liruited.
untitled h1
5..1 participation of children

Only patients 18 yeat's of age or olcler rvill be enrolled orr tliis shrdy, since postmenoparxal breast cancer cloes rot occur in children.  
5.5 Sources or \'Iethods of Recruitment Palients rvill be recnriletl tlu'ouqh screeni fbllorved in
untitled h1
5.6 sturly enrollment procedures

A copl, of the iustitution's lRB-approvetl intbrrned cousent docrurrent ancl wntter ou file tleft"rre iustiticntiou for auv changes niacle to the urtonued consent for this tocol nrust be rt the auv partrcrl)irtlng rnstihrtron lnav elltel patients. Corrseut fonus 1iro1 ()t' llse af a participating iustitution musl be reviervecl and ,lpproved bi, the OIIRS Regulator^y Allhils It'lanager anrl all docruueuts nrust be lec.eived (i.e.. IRB appror,ed documentation. IRB
approved conselrt forrlt. See Section 15.2 lbr a courplete [st of regrrlatc]r-v iterffij.  
instinrtions rvill tlu'ough the OI{RS Registratiorr Desk Patieut derrrouraphic iutor"rnatir-rn. the gibilit"v checklist and courpletecl srgnanrre pnse of the cousent tirnu and registration desk.  
snrdy nrurrber will that the palieut is registratiou.  
atlditioual Once the lie issued.  
consiclerecl sotu'ce docurueuts if requested by OHRS rurnl be seilt to the OHRS Registration Desk verifies eligibility. a rurique patient The patieut u,ill not be ideutitletl by uarne. Tlris is the poirrt r-ru studv. Patieuts uurst urlt starl protocol trcatureul prior to
-.  
If a patieut does not receive anv protocol therap,v, baseline data rvill be collected and sub:nitted ou tlte pre-sturiy and fcrllorv-up electronic case reporl tbms (eC'RF). The reason lbr uot starting prr:tocol therapy will be docruueufed in the "follop-1p eCiRF". Case report tbnn completiou irrstnrctions ancl training rvill be provicled to each parlicipatiug iustinrtion priol to stucly activation at the participating rnstitutiou.
untitled h1
6. study parameters

The followin$ tests and evahmtions will Baseline (i.e.. pre-studv) evahrafions mrnt prior to ltrerapv. rurless othenvise inciicaled be perfonned accordirlg to the schedule lrelow.  
be perfonned no louger than 4 week,s (+/- 3 dflys)
irr orre of the footnote* bek:rw the table.  
| Er':rluatiour                                                                                            | Prrsfud"v            | Every'{ weeks (prlor lo e*th cyrl* be1'ond cycle 1)   | el.ftet fhe {iryt I rvreks (*frer first 2 cycles)   | f,r'er1 12   | End of   |
|----------------------------------------------------------------------------------------------------------|------------|-------------------------------------------------------|-----------------------------------------------------|--------------|----------|
| \Yeeks                                                                                                   | Trentrnenf |                                                       |                                                     |              |          |
| hritial Histor:,, and Phl sical                                                                          | x          |                                                       |                                                     |              |          |
| Llteriru Hislol.1, a|d Physical                                                                          | -\         | X                                                     |                                                     |              |          |
| Toxiciry A.sressnrent                                                                                    | x          | x                                                     |                                                     |              |          |
| ECOG Pertbmrance Statu^r                                                                                 | x          | x                                                     | x                                                   |              |          |
| \\reieht and Heislrt'                                                                                    | x          | x                                                     |                                                     |              |          |
| CBC. difiereutial. rrlatelets                                                                            | x          | xt'                                                   | x'                                                  |              |          |
| Senun Clrerrisrriesj                                                                                     | X          | X,.                                                   | x'                                                  |              |          |
| Liver Eru,."'trteso                                                                                      | x''        | x"                                                    | x'                                                  |              |          |
| EKC                                                                                                      | x          |                                                       |                                                     |              |          |
| Radiographic A-ssessrtrent s                                                                             | \          | x                                                     |                                                     |              |          |
| Circtrlating Turrror Cellso                                                                              | x          | x                                                     |                                                     |              |          |
| ('orlelative Blood Studies'                                                                              | X          | x                                                     |                                                     |              |          |
| Archived l'urnor Tissue                                                                                  | x          |                                                       |                                                     |              |          |
| Ttuuor Biopiv- { if accessiblei                                                                          | x          | x"                                                    |                                                     |              |          |
| PillDian                                                                                                 | x          | ](                                                    |                                                     |              |          |
| Record collcolrutant medicatir:ns                                                                        | x          | x                                                     | x                                                   |              |          |
| Cour1rliance Assessnrent                                                                                 | x          | x                                                     |                                                     |              |          |
| Srrr-l ir-al                                                                                             | x          |                                                       |                                                     |              |          |
| l. Blood presstu'e should be nrouitored weekll' druilg the iilrl cycle. lt{ea.sruerner[s rnaybe obraited |            |                                                       |                                                     |              |          |  
Circtrlating Turrror Cellso x x  
('orlelative Blood Studies' X x  
Archived l'urnor Tissue x Ttuuor Biopiv- { if accessiblei x x"  
PillDian x ](  
Record collcolrutant medicatir:ns x x x  
Cour1rliance Assessnrent x x  
Srrr-l ir-al x  
l. Blood presstu'e should be nrouitored weekll' druilg the iilrl cycle. lt{ea.sruerner[s rnaybe obraited  
oulside of the treatinpr physician's ot{ice. lrou'eter. unlst [:e docunrented in the patierrt's diar1.  
\:leastu'enrettrs shoriltl be nrade usrng a calibrateil elech'ouic detice. turless perforrrred in a doctor's otfice  
rvhere a uramral trlood pressrue lneaslrerlreut is accepfable.  
Height to l:e ureasured ouly at trnseline.  
Setrutt clteluistries itrtlutle: Sodirul. Potasxirurr. Chloride. Bicarborrate. Calcirrru. Glucose. BLI}'tr and  
Creatinine,  
,1. Includer: total bilimbin. AST. ALT. alkaline phosphatase. albusrin and total protein.  
5. Radiographic assessulente rvill be selected by the attending physicial a"r clinicalll. indicated and iu  
accordance u'ith the crireria for nunor rueasruelllellt asses,\menls. Confirnutory scans should be  
obtaiued'. 4 tleeks tollou'iug iuitial docrurreutation of resporrse. R.e*pouse rvill be evaluated evern'-J  
6 1  
cy.cles.  
See Sectiorr l1 lbr saurple collectiou arrd analysis ntetltod$.  
Otrtain archivecl ftuuor tissue (ti'orrr tirne of original diagnosir) tor iuurrunohirlochetrical nllal-vris: carl be otltained at artltiute after eruollurent. Selld to Cancer hrstitute of Nerr,Jerse-v isee Seuion I li. Ifbiot,.L@dpriortorecerr.irtgsnrdvtlrerap1,-nrtdprior1ostar1ofCycle2 Send to {see Section I l)
Phase I{I Trial of Letror"t.f ancl Sorat'enib ,I as Firsr-Lirre Therapy itr postrnenopaural
\\'otttett u'ith Hot'rttorte ReceliG;Fosiiile Localll'.A,dvarrcaffi[letairaric Breast C'aucer
-
9. Follou'elery -l tttr:trlltr to defenllille status. .{ telephorre call cnu be rriade tiu rtuliral ttlllon-rr1l.  
10. { ld days prior to tleatttell I l. ! : day's prior to re-treatrneut 12. As cliuicnlly indicared,
untitled h1
6.i efficncv assessments

'I1le plimary ellicacv endpoirt is the clilical benefi{ rate CIf letrr:zole aud sorafbnib in this patient populaticlrl. Clinical trenetit mte (CR + pR + SD r 6 ntoutlis) will be tJetemrined for ffi tI ft iilI' ::li*"..H,ffi1$i,' i",H Jil\#;I i:.,ffi verit-v or quesliou the t}ralitatir.e nature of the apparenf resporlse" For sutrjects with skin lesiotts. photogmphs should also be sent tbr rcr,ielv as well. Filurs antl,or CDs slroulcl be mailed to:
untitled h1
7. trertment plln

7.1 General Considerations  
Trcahuent rvill be adtniuistercd on an outpatient basis. Patients r.vill be instnrcted to stafi study dnrgs ou Day I of each 28-cla1, lrealureut period. One cycle is defined as ?8 days of treatruenl. Prior to starling a cvcle. all patielts urust conti.nue to meet all iuclusion criteua
(see Sectiorr 5.1). No inr,estigatioual r;r conur-rercial agenls or therapies otlter tharr those described belorv uay be adruiuistered with the intent to treat the patient's uralipnancv.  
Patients will receive treatutent until it is no longer of benetit to theur. Patients may disconlinue lherapy at auv titre lbr ruly reasou.
untitled h1
7.2 dose determinution

Doses of sorafenib will be detennined by the phase of the shrdy iu rvhich the patieut is eruolled. Leh'ozole is given at a fixed dose of 2.5 urg daily fcrr lroth the phase I and phase II
portious r"rf the study.
untitled h1
7.3 treatment administrtion

Treahnent *'ill reqtrire tlaily oral adruinistration of medications ou an outpatient basis.  
Tteatmeut utay be clelayed lbr up to lrvo r,veeks tor recr:very fi'r:rn Grade 3 or 4 adverse evenfs. If patients do not recover r.vithin trvo weeks, the patient will be removetl fiom shrdy.
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7.1.1 letrozolc

Patieuts will fake lerrozole orall!'at a dail.v dose of 2.5 nlgiday on Da.vs t tluorrgrh 2g.  
Lelrozole may be talten rvith or r,vithout tbod. Tablets shoulcl tre sr,vallowed whole with 8 omces or 250 rul of water.  
Patietts n'ill be provided with a Medication Diary tbr letrr:zole. iustnrcted iu its use, and asked to bring the diary with thern to each appoint*reut.
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7.3.2 sorafenilr

Pntients rvill also fake sot'afenib orally at a daily dose to lre deterurirretl based upon the phase of the shxly that patient is eruolled (See Section 7.4). Sorafenib will be taken ou Days I tluougdr 28.  
Sorafenib shr:uld be taken on au empty stoluach^ at leasf I hour tiefore or 2 hours alier a rrreal. Tatrlets should be swallorryed whole. uot cnrshecl or chewerl. rvith S orulces or ?50 nil of rvater. Sorafenib should not tre taken with grapefiurt juice.  
Palienls rvill be prr:vided rvith a lvledication Diary for sor:afbuib. irrstnrcted ir its use.  
and asked to bring the dial-v rvith theur to each appoiltrnent.
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7.3.3 missed doses

If pafieuts voruit afler taking letrozole or sorafhrib. patieuts should be instnrctetl not to retake the dose. Patieuts shr:uld take the nexl schedulecl dose of letrnzole or sorat'enib therapy.  
If a scheduled dose is missed. patients shorrld lre instrtcted to take the dose as soor as reureutlrered" If it rs uear the tirne of their next dose they shorrld be instnrcted to skip the close and restuue ttreir tnual dosing scheclule. Patieuts shoultl not double tlreir dose to catch up ruissed doses.
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7.{ phase i dose tr{odilications

For the Plrase I dose escalation portion of the trial. patieuts will be eru*ollecl iu trvo cohorts (Level 0 ancl ll rvith the lbllor.ving close escalation nrles:  
Dose Level0 The first tluee patients r.vill starl al Level 0.  
o If 0 patieuts expedence dose-lirniiing toxicity (DLf) duriug cycle I. the dose will be escalated to Level l.  
r If I of the tirst 3 patients experience DLT in cycle l. rve will expaud the cohofi and 3 more patients will be heated at Lel,el0 for a total of 6 patient.s.
. If I of these 6 patieuts expelieuces DLT in cycle l. the dose will be escalated to Level l.  
o If 2 or urore of the patierrts irr this coh,rrt experieue.e DLT iu cycle l, we will have exceeded the rrraxiruuur tolerated dose (lv{TD) and rvill de-escalate to Level -l aud eruoll 3 patieuts. If no patieuts experieuce DLT during cycle l, this will tre the recr:nunencled phase II dose.
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dose level i

The second cohort of tlu'ee patieuts will be stafied according to the nrles above aud eruolled as follolvs:
r If 0 patients experience DL'I at Level I in cycle l. this will be olr recoruuended phase II dose.  
r If I of the tirst 3 pntients experieuce DLT in cycle l. we rvill expaud tlre cohofi and 3 urore patients i.vill be treated at Level I fbr a total of 6 patients.  
o If I of these 6 patients experietces DLT in cycle I . this ivill lre our recouuneuded phase II dose.  
r If 2 or more of the patients in this cohort experience DLT irr cycle I. we rvill have exceeded the N'{TD and Level0 will be the recomrueuded phase Ii dose.  
Each of the trvo dose levels of soraferdb will be gir.eu rvith letrozole at ?.-5 rng orally' daily as outliled in the ckrse escalatiou schedule listed iu the lbllowing table:  
| Does Ercalttion Schedule   |                              |
|----------------------------|------------------------------|
| Dose Ler,el                | I)ose of Sorafenib           |
| I.,el'el I                 | ,100 urs po ttvice a day     |
| Ler,el0                    | ;100 ruS po clailV           |
| Level - I                  | 400 nis po everY otlter clav |  
Intrapatielt dose escalatiorr rvill be allorved for patients eruolled at Level 0 and if they do not experience DLT duriug Ciycle l. they can escalate to Level I for C.ycle 2.  
DLT rvill be evahmted in the first cycle of therap-v ancl defirred as: Grade 3 or 4 uon-heruatologic toxicit,v (except alopecia. narxea. emesis that resolves to { Grade I with syurptomatic tleatlnenl) or Grade 4 heuratologic toxicity that is thouglrt to be related to soraferrib.
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7.5 phase ii toxiciq- nnd

Patients rvill take letrozole ?.5 nrg orally daily" aloug rvith sorafenitr at the uraximrmt loleraled dase to be deler-nrinecl fi'our the Phase I restrlts.
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7.5.2 sornfenib dose n{otlificafions

Sorafeuib specific rnodit-rcatiorls are outlined in the lbllowing tables:
Phase I{l Trial of Letrozol.f*,r..1 s.,rnl.,,i[I a: Filrr-Liue Therapy'iu Posturelopaural
\\'otttett nitlt Honttotre Receptor-Poiiiir c Loc.rlli' A.lvlll.e.Iorlleta.tatic Brca>t (.urcer PI:  
| Table 7.5.2.1 Dose llodifications for Sorrfenib for Hand-Foot Skin Reaction Skin Toxicitl,Grade Occurreuce Suggerted Dose }{odificatiou Gade l: Nrutbness. dysethesia. prar estlresia. tingliug. pairiless suellirrg. erlthenra or disconrtbrt of the hards or feet u.hich does not disr-rrpt the palieilts lonual acti\il_v .{ny krstitute *uppot'live ilteasrues itnmediately and corrtinue sora lbnib occlur"ellce trEatluent 0rade 2: Painfirl eryrtherna and sr'r,elling of the hands or feet altlor dircorufbrt all-ectilg the pntient's nonnal activities l" Inslitute supporttt:e rnefl$rres and consider a decrease ofsoralbrrib by I occwTence dose level. e If toxicit,'tenrrx fo grade 0*l after do*e redtrction. increase sorafeuib to full dose (per original dosing *chedule) after 38 days r lftoxicily does ror retrulr to grade 0-1 despite dose reductiorr. irrterr"ttpt soraferrib freatrneut for a urininrrrur of ? days. rurtil toxicity has resolr-ed to grade 0-l r[rhen resunring treatrneul alter do*e iutenrrpliorr. t"e$tune sorafenib at the rrext log.er dose level for ?8 da1,s r If toxicity is rnaintained at gracle S-1 at reduced dose. increase sorafenib lo firll dose (per origiual dosirrg schedule) afier 38 dals -nd .rd As lbr first occllflelce. txrt upou reriutrilg sorafenitr trentrnent. decrease -  clf -l occtuTe[ce dose fo the uext lower dose level irdelinitelv -l"rh Decisiol rrhether to discontiuue soratenib lrefftulent slrould be rnade based on clirrical jrrdgeuteui and patieut pretbrence occtuTence Grade 3: Moist desquanratiou. t{ceration. blistering or severe pairr of the halds or ieet. or severe disconrtbrt that causes the patient to be uuatrle fo rvork or perfonn aclivitie$ of daily lirirrg IO' Llrtitule srqrportite lneasrreri flld ir[€l"t'upt sorafenit: treaturenl for a occl^uleilc€ ruiniuruur of 7 days and rurtil toxicity hns resolr.ed to 6rade 0-l o \Yhen resunring rreahlent afier dose interruprion. {estutre sorafenib at the uext lo*'er dose level for 28 days o Iftoxiciry'is nraintairred ar grade O*l at reduced dose. ilcrease soratenib to firll dose (per original dosing schedrrle) after 38 days As for t-rst occrul'euce. but upon resuuring soral-euib tteatrrrnt. decrea-se 2.,1 tlose to tlre lrexl lorver dose lerel incletinitelv occtul.ellce rtd Decisiou rvhetlrer fo clisconfiuue soraferrib treatuleul should be rnade -:l oc{.tuTerrce base<l orr clinicnl judaenrent aud patient prefereuce *Patients,"l'lro develop glade 3 teverrchills. gratte 3 eler,alion of hepatic trarxaurinaser with ALT ard AST < l0X   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
*Patients,"l'lro develop glade 3 teverrchills. gratte 3 eler,alion of hepatic trarxaurinaser with ALT ard AST < l0X
ULN. grade 3 hlperlipaseuia ot' hlperanrylasenria u,ithout clirrical or othel er,idence of palcreatitis. grade .3 lerrkoperria. or grade 3r'grade ,l lymphoperda uuv corrtiuue study trenturellt u,ithout iltenrrptiorr ar the discretion of tlre inlestigalor.  
  
PI:  
  
| Toxicifi'                                                                           | Gracle I                                                                                                                                                                                                                    | Grade 2                                                                                                                                                                                                                                                                                                             | Gruele 3             | Grade {   |
|-------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------|-----------|
| l{onhematologic                                                                                     | C orrtinue at the                                                                                                                                                                                                           | Coutiuue al tlte                                                                                                                                                                                                                                                                                                    | Withhold dose turtil |           |
| same do.se level.                                                                   | toxicity is grade s l.                                                                                                                                                                                                      |                                                                                                                                                                                                                                                                                                                     |                      |           |
| same dose level.                                                                    | llren resurne treatrneut at tlte saue dose level. If patieut ex1:eriettces a secorrd grade 3 toxicitl,. rvittrhold close rurtil taxicity is glade < l, theu rechrce dose the uext lower dose level ancl restune trcatmeilt. | Wilhh0ld dose turlil toxicit-v is pnade < l. then reduce dose to tlte next lorver dose level aurl resunte lreatmeut. or discoutitute at tlte discretion of the principa I investigator atler discussion with shrdt'sponsor. If toxicit,v does uot resolve rvithirr 2 rveeks patient rvill discoutimre tr^eatrrrent. |                      |           |
| If toxicit-v does uot resolve rvithiu 2 lveeks patient rvill discontinue treatment" | If a second tr:xicity occurs the patient r.vill cliscoutiuue treatrnent.                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                     |                      |           |  
Trble 7.5.2.? Dose llodilicltion for Sorlfenib Associtted Non- HemttologicToxicitv l*:1,111;tii;i,1::i::,lHr:l;Hi::il.;;t}::;t:?l::lflil:,:"P'si':,e':r'pa.,iar  
| Drry I of An-v C.vcle                             | .\)r{(' ..:: 126QipL aud or            | Hold Treatruent                                  |
|---------------------------------------------------|----------------------------------------|--------------------------------------------------|
| platelets ",: 100.000,'trl                        |                                        |                                                  |
| * CBCs shoulclbe repeatecl rveekly until recovely | If corurt recol.ers rvithiu I          | Resuure treatrnerrt at full                      |
| rveek                                             | clo.se                                 |                                                  |
| If count l'ecovers withirr 2                      | Reduce I dose level for all            |                                                  |
| rveeks                                            | srrbsequeul c1'cles                    |                                                  |
| If corut cloes not recovel'                       | Discoutinue prr:tocol                  |                                                  |
| rvitlrin 2 weeks                                  | tleaflneilt                            |                                                  |
| An-vtime during                                   | Febrile episocle (-.' 38.5"C)          |                                                  |
| treatment                                         | accoruparied b-v ANC couut ",; l200ipl | Ret{uce I dose lel el tor all subsequeut cycles. |
| A subsequent febrile                              | Discorrtinuntion of protocol           |                                                  |
| neutropenic er.'eut                               | therapy                                |                                                  |  
Table 7.5.2.3 Dose llodification for Sorafenib Associatetl Hem:rtologicToxicitl Table 7.5.2.J.A Dore Iloclificrtion for Sor:lfenib Associ:rted HemttologicToxicit.l'  
| "I oxicitl'                              | Gnrtle 1          | Grarle ?                                                                                                                                                                                                                                         | Grade 3                                                                                                                                                                                    | Grntle {   |
|------------------------------------------|-------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------|
| Hematologic toxicifies not Iisted lbor-e | Corrtinue at the  | C'ontiuue at the                                                                                                                                                                                                                                 | Withhold close rurtil                                                                                                                                                                      |            |
| saure close level.                       | saure dose level. | toxicit,v is grade s 3. tlren resuure treatment at the sarne close level. Ifpatieut expelieuces a secoud pacle 3 toxicity. rvithhold tiose rurtil toxicity is grade { 2. then reduce dose to the next lorver dose level ancl restuue treatruent. | Withliold dose until toxicit.v rs gn'ade < 2. then reduce dose to the uexl lorver dose level and resurne treatruent. or cliscoufinue at tlte discretion of the prirrcipa I iuvesti ga tor. |            |  
iifi::"Xlitil" ".""i:::H ::ilffi f :ilm,:,:lx: ?rlt:liJ;i" Po s'fr':re,opa'lriar O',7
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trble 7.5.2..1 mnnlgement of treltment

| Grade                                                                                                         | }I*nagementlNext Dose                                    |
|---------------------------------------------------------------------------------------------------------------|----------------------------------------------------------|
| Grade I                                                                                                       | ('r"rusicler increasecl l]P monilol ing                  |
| Grade 2 aspuptontatic and                                                                                     | Begin anti-ltlperteusir.e therapy and cotttirttte agent. |
| cliastolic BP.r I l0 rruu Hs Grade 2 syuptoutatic anclor persistant OR Diastolic BP.: I l0 rrun Hs OR Grade 3 | Ageut should be held rurtil syrnlrtours resolve and diastolic BP s I00 nuu Hg; also tleat patient with arrtiliyperteusives and rvlteu agent is restartecl teduce by I dose level. If diastolic BP is not controlled (< 100 uuu Hg) on ther.lp)r reduce arrother dose level.                                                          |
| Grade -l                                                                                                      | l)iscoutinue therap-v.                                   |
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7.6 concomitant iliedications

A preexisting coudition is oue that is presert at the start oi the study. Any uedicatiotls
(including but not liruited to prescription medicines. over-tlte-cotutter ntedications. zutd herbal supplements) rcquired lbr a patient's pre-existing coldition nrusl be approvetl by shrdy personnel. Any rnedication proven to have sicle effects rvith either letroznle or soraltrrib rvill not tre approvecl wtrile the patient is parliciparing in the sttrdy.
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7.7 supportive cnre guidelines

No other cheurotherapy. homoual therapy (other tltan lettozole). racliatiou therapy or experimental medications will lre pemitted rvhile patients are pafiicipating ori this shrd-v.  
Svrnptouratic alemia should be treated rvith appropriate red blood cell strpport and trausfiniott is recormuended if the heurogloliiu falls belorv I g'tdl' Altenrately recoutbinartt er).'tlx'opoietin may tre nsed if desrred b-v the patienl'$ physician^
Tlu'orubocl"topenia sliould be treated corsenatir.ely. h the al:sence of bleeding or a planned invasive procedrue. platelel transfitsious should ouly be given for a platelet corurt belor,v 10.000 cells.,truu''. If iuvasive procedues are plarured or tlte patient develops bleeding. plafelet transfusions shorild be admiuistered iu accordauce rvith standarcl of practice. uiually uraintaining a platelet couut greater than 50.000 cells,'uurr3.  
Nutritional assessureut and ps-lchological srrpport: Refractor.v neoplasrns are couunouly courplicatecl b.v-' urahrutrition. Patients r,vith rveiglrt loss or evitlence of wastiug s\'ndrome shoulcl have a uutlitional cousuh. Patients who are havurg euotional clifficulties dealing ivith their treatment. aurl diseirse. or those patieilts rvho requesi assistance. rvill be ret'enecl to a Social Worker tbr er.aluation artcl supporl.  
im:r-ifiiil;j,|;,:"i:::HiJl;'ffifilm,:l^|;i":'J::*F:xi.';i"Pos'ir,erropa"rar
-
I{a,cl-ibtit skin reactiorr $alurar-plallar erl.tluoclysaesthesin) aud rash lepresent tltt-" most couunen adverse ctnrg reactions rvith sorateuib. Rash aucl hand-tbot skin reactiort are
,sually ('T6'AE Gracle I ancl I and geueralli' appear cluLiug the tirst six rveeks of trealtneut rvith sgrafenib. iv{arragegreut of clenuatologric toxicities urav inchrde topical therapies for slruptouratic reliei temporary treatmeut iuternrptiort anct,or dose rrrodificatiott of sorafenib' or"iri severe orpersisleut cases. pemrartenl discontinuatiou of sorateuib (see Section 7.5.3)'
Pennaleut tliscontiruatiou of therap.v clue 1o haud-lbot skirr reaction occun'ed in 3 of 451 solatiuib patiertts.  
A1 iucreasetl inciclence of hlpertension rvas observed in soralbnib-treated patients' I{perlermion was usually rnild to motlerate. occrured early in tlte cotuse of tteatmertt- attd ruoi orrr"r.oble to p&rragemetrt rvith standard ailtih)?ertelrsive therapy. Blood pressure shoulcl be monitolecl nopitc,r'ecl lveekly tbr the tirst 6 rveeks of therapy nucl theu ott a reEular. basis and treatecl. if required, iu accordance rvith stanclarcl rrredical practice. hr cases of severe or persistent liyrerteusiou. or hlpertensive crisis despite adequale urtilypertensive ilrerap,v. penrraileut clisr-:onliuuariou of soralbnib shotrld be considered-Pelualent discontimratior r:f therap-v clue to hlpertensiou occtured iu I of '{51 sorafiilib patients.  
An ilcrease i1 t1e risk of bleeding ulay occru tbllorving sorafenib aclrrtiuistlatiou- Tlie iucidence of severe bleecling eveuts is uncorutrton. If arr-v bleedirlg eveul necessilates lredical intereltiol. it is recourrneucled fhat pemlanent rliscr:rttimratir"rn 0f sorafeilib be considered.  
Teurpomrv or pemrarlelt discontiurmtiou of soratblrib should be considered in patiertts wlto develop cardiac ischernia andior inthrctiorr.  
Sorat'e1itr therapy shoulel be cliscontutuecl in patients rvith gastoirltestiltal pertblatiorr.  
7.8 Adherence/ComPliance patient ct"xnpliauce n aaitv selt--adnriuistmtiou of ttre oral tatrlets will be assessecl at each clilic visit. patielts will be given n nredicatir:n cliary and instructecl to fill ont horv ruary talrlets (letrozole aud soratenitr) rvere takeu each da-v- aut{ the time of da,v tlte dnrg was taken. At the encl of each c-vcle of treaturent. the acnral afilotult of utused dnrg ivill be courparecl to rhe alticipated arnouut oltutused dttrg aud the patierrt's utedicalion diar-v.  
8. Toxicify }lonitoring lnd Adserse Event Reporting lll patients rvSo receilie one close of prolr:col ilr*topy will be evaluable for assessurettt of toxicity. pr.ior to each cl.cle the h'eatiug ph,l'siciau will flrlly assess the patient's condition with
,"*pu"i to possible treatineut related toxicities. All adverse evelts. 'uvltether obserced b-v the ptrysicial or rep,:rtecl b,v the patient. occun'iug dru'ing tlte aclive porliol of tlterapy, or up to 30 iu-r*r .ft.r the last close of tr.otmerrt will be gratied try n uturrerical score accordirtg to the NCII's C6uun6p Terlunologl' Clriteria tbr Aclverse Events (CTC'AE)- Version 3'0 firttp:,,,cteo.cancer.govr'ieporlingictc.html) aurl recorded iu tlte patient's rnedical record.  
  
Acl'erse e\iellts rvill be recorded otr eleclrorlic case" repol'l t'orrus itt accr:rdatlce with I studyspecitic data capflue Plal.
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8.1 definitions antl reporting requirenrents

8.1.1 Definition of Reln(eel There is a reasonable possibility that the dnrg caused the adverse experieuce. That is.  
rhe evenr is judgecl tr1, 11r* inveitigator to be possitrly. probatrll' or det-ulitely related to the treatruent.
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8.1.2 definition of tlnexptcted

fuiy' aclverse clnrg .*p*ii.r.* andlol specificity'. that is ur:t included irr the L:turent iuvestigator's broclitu'e artttr or package insert.  
8.1.3 Definition of Atlverse Evtnts (AE)
An aclverse event is any e,r.errt associatecl rvith the use of a clntg in ltruuafls' whether or not colsiclerecl dnrg reiate.l. inclucling the fbllorving: fui adver'se eveut occuring in the corlrse r:f tle r15e of a dltg ur protbssional practice: an adverse event occturing fi'r:tu d1,g ouerclose r.vhether accidental or intentioiral: au adver$e event occturing frotn durg rvitlidrarval: ancl any thilu'e of expecletl phannacological action' 8.1.{ Detinition of Serious Atlverse Event (SAE)
A serious adverse everlt includes any evettt that:
.Rcsrrlls in deotlt" Is I ife-rl t rea t et rir t g NOTE: Ttre ienu 'lit'e-threateling' retbrs to atr evenf druing which the sutrject was at risk of death. It does no( reter to ar event rvhich hyrolhetically might have catned cleath if it hacl been ruore seYere' Reqtires inpctlient lrcspiloli:dliort or proloilg{ttion o,f.efisting hospitoli:otio.n' NOTE: I11 geperai hospitalization ureais that the sudect has been detained
(usually ur,-ilr,rrg at least arr ovemiEdlt stfly) at the hospital or eurergeucl'rvard for r:bseratiou or treatment that would not have lreen appropriate irr the ph-vsicial's olfice or out-patient setting. Courplications that occrtr dutittg Lospitalizatigl ar.e AEs. If a coruplication prolo-ngs trospitalizatiorl or fullills arr1, o11r"1. serious criteria. the eveiit is serious. When irt cloubt as to whether hmpitalization occrulecl or was [ecessi]ry" tlie AE shonlcl be cotsidered sedotu. H0spitalization for elective ffeatmellt planned prior to shrdy enrolhuent is neither an SAE nor att AE'
Refiilts hr pe.rsistettt rtr significnnt di.s*bilitt: oy itrtopority.  
NOTE: T5e telu clisabiiity' rleaos a srrbstnntial disnrption of a person's ability to conclucr nor:ual litb frrrictiots. This definition is not inteuded to include exper-ierces of relatively rninor uredical significance sttch as rutcoruplicalecl il,}:::K'Iiii1:j,T,x"i:f-mff:riif$H,}:,}:?[^}[:1r:;,'Postrtrerropatrsal N',E
headache. nausea, votriliug. diarr{rea,  
  
sprained anlile) rvhicli uray ilterfere or not constitute a sutrstatrtial clisnrption.  
iutluenza. and accitleutal trauma (e.g.  
  
prevent everlda.v lit'e frrrrctions bttt dcr Is a congenittl urcnuth'or ltirth de,{ect.  
Is an importartl ntedicol et:ettt.  
An event niay be consiclered an iurportalt ruedical evertt when. trased ttpott appropriate rneclical judpnerrt. it ruay jeopardize the patient artd rnay reqtdre ruieOicat or sru'plical iutelention to preveut one of flte outcotnes listed in the rletinitioq. Exanrples of suclr rnedical et euts include allergic broncltospasrn requiriug inteusite freafment irr an efirergellcy rc]otn or at home. blood dyscrarias or counrlsions that do not result in inpatient hospitalization. or tlte der,elopurent r:f clnrg depenclertc-v or rlutg abuse.
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8.1.5. definition of arlverse drug

All loxious aud rurintentiet{ respouses to a rnedicinal prodtrct related to any close shr:ukl be colsidered adverse clmg reactions. The pluase "resporses to a uredicinal prodttct" nreills in vierv of the investigator aucUor compauy tltat a catnal relationship betrveen a rpedicinal pnrduct ancl an atlvelse eveut is al least a reilsonat"rle possitiilit--v ;urrl that the adrrerse event is associated rvith the use of tlte dmg.  
Renction (SADR)
event that meet.s any of the criteria tbr a possible catxal relationship to the sttrcly 8.1.6. Definition of Serious Adverse Drug A Serious Adverse Drug Reaction is att seriousness as prer.iottsll, delined ancl has dmg.  
8.1.7 Requirements for Repo1lling of Serious Adverte Events:
All SAEs occrur-ing after a I iroclt,"t has been utilizecl musr be rvithirr 24 horu's of the PrIrc[al htr,estigator's awarerless artd follorving rtrinittturn infcrnnalir:n:
l. The naure and cr:Irtact infonuatiott of the reporter l. The naute of the sttrdy dnrg(s)
3. A descriptiorr of the reportecl SAE
4. A patieut iderrtified [-r-v one or rllore of the fr:llowing:
a. Irlarrre or initials b. Patie[t rtru.rrtrer c. Knor.vledge that a patieut cl. Age e. Sex reporteri to I
ruusl inclucle the  
rvlro experiencecl the adverse event exists
iifi:.1'llilil;i,T,:"ilf.H:;f;;fi rilm,*m: !;:.-l'filffi " Po s'lr*e'opa"rar 5. ;\1 investigator assessrlL'ut of study clnrg causality. For sttrdies lvitlr courbinati.:n tlierapy. a separate causalit-v assessnlent .should be provicled fr:r each shrdl' d1rg.  
Aclditioual data r.vhich would aid the review aud causality assesstneul of the case iuclude trut are ncrt lirrrited to:
The clate of ouset Tlre sel'erit-v The time fi'onr at{ruiuistratiou of shrdy clnrg(s) to starl of tlte event The drrration attd otrlcoute of llte evettl Any possible etiologv tor the evettt The ftral diagrrosis or s1'ndrrure. if Llorvn Action(s) taken. if auy For bliuciecl studies. the Priucipal hrvestigator rvill pror.'ide fhe treatuent assiqruttent npou request for parients rvho experiertce SAEs. The Pritcipal Investigator rvill provide the hnal treatluent assrgnurent irrunecliatel-r- after tlte encl olttre study.  
8.1.8 Expeditetl Reporting of Other Safety Information to Bf All palticipatius insritutiorrs rvill report all S.A.Es to the OHRS at the!  
I The OHRS rvill be responsiLrle iirr tirtrvarcling SA repods to a
;pfirtlffiate -uroups as needed as clescribetl iu Sectiorr I' 1.9.  
T[e O]{RS rvill be respousible lirr lortarcling SAE reporls tot he strtdy sttpporler The hrvestigatori Sponsor shall repr:r"t to Bayer rvithin 24 horus of the iuvestigator's awareness r:f other evellts such as:
An adverse evettt related to studv specilic procedru'es A1y netv and iruportant eveut related to treatmeut rvith the study dnrg(s).  
.{1y prepnranc-v cluring rvhich a female patient was exposed to the stucl,v clnrg(s)
.fuiv preguranc-v in the partrer crf a urale patieut, where the ruale patiettt rvas esposed 1o snrcll,' dnrg at the tiure of couceptior or cclnception occrtrred rvithiu two weeks of the last dose of strrtl-v drug(s).  
\*'hen follow-up informttion becomes available for r previousl-v submittetl safety report, the report form shoulrl be uptl*ted with the new information anrl sent to Bayer.  
The Investigatorlsponsor mfl-v report SAEs using either:
A1 ADEERS tb1111 (Adverse Event Expetliled Reporliug SystemJ available at http : r'1 ctep.csncBr. govi l epofi iI] giadeel's "htrnl oR
A N{etlWatch fonu available al httt:: ""rvrvrv.lrh.sovilneclwatch ii]il:*1ili1;i,1",["ilf.H::i.:Jiii:'i].m,:I^|l;]:?'Ji.I',fl1l];"Pos'lr':re'o,a'lriar n,,I  
  
The Principal hrvestigator cotlurtits to responcl prourptl)' to atr,Y qtler-v tlolr J
regarding SAE rePorts.  
8.1.9 Repol.ting L'nexllected and/or Serious AdYerse Events to thel aclverse evellts the last dose of ffiecl..tdet.irredtlelorv)atltl.or'.seriolts'.(t1efirledtleloi.l.)
occrulitg,lturue the actile poltion of tlterap!'. or trp to J0 da-Vs after 8.1.10 Reporting l-:nexpectetl and/or Serious Atlverse Events to Institrrtional Revierv Board Eveuts rvill be promptl-v reportecl. in rvritiilg. t(] the local IRB itt accordauce r'vith IRB
ffi; il;;iJ;I, o..,u* rire IRB rvill be riorified rvithiu 24-hotrrs of initial receipt of
. r- - -. --- ^-.+.-l +^ rl^^ ir*r"i"r. [rrtt*tecl attd"ol serious adverse eveilts must .tre :tpo1f:.d,to th1 sciences Insritutioual Revie$, Boarri withiu trve (5) dnvs ot'
@.ertt,\\rt,itlerrto1lorv.rr1)reportsat.eieqttiredlvlrerraclc1itional rutbnuatiol is needed to hllll'cltaractetize the eveut'
untitled h1
8.1.11 reporting serious .tdverse evrnts

8.1.11.1 Sornfenilt  
The PI is responsible tor notif-viug the FDA of any* ach..erse experience associated rvith the rrse of soratbniti that is both serious g! truexpected /1.e., tot listed in tlrc lupotiuib itn)e:;rigotors ltroc/rtrre). a$ soort as possible attd in no evetrl later than l5 calendu da),s afler the PI's discovery of the event. Each written nr:rtificatior ma]-
[.le submitted o11 FDA Fonu h.{ed\l.atch -1500A
http:,,nryr... (fax \# I-800-FDA-0I78)
Tlre PI shall also uotifl, the I]DA by telephoue or by thcsirnile trarsmission r:f any ulexpected thtal r:r lit'e-tlueateniu.q experieuces associated rvith tbe rme of tlte clmg. as sooll Rs pos.sible but no later than 7 caletrlar clavs fi'our the PI's discovery of the eveut iribtuation.
untitled h1
8.1.11.2 letrozole

T[e PI is responsible for uotifying the FDA of any t]nexpected (lot liste'd in the packoge irr.rerl) serious adverse eveilts that ate sssociated (defirritely, probably or possibly related) rvith the use of lehozole. urusl be reporled to the FDA rvithin I0 brniuess clays usiug a FDA Fomr MedWatch 3-500 fomt hltp:;, rvrvrv.fda.govluredrvalcUsatetvr'3500.pdf (fax \# l -800-FDA-01 78).
untitled h1
9. treatnrent evrlutionlclriteria for response

For the ptuposes of this shrdy" patients shoulcl be reevaluated tbr respouse follorving ever-v third cycle of therapy. In acldition to a baseline scan, conlitrnator): scans should also be obtained not less than 4 weeks tbllowing initial docuneutation of r:trjective t'espouse.  
Resporxe arrcl progressiou rvill be evahrated in this studl' tning the iutetrtational criteria proposect by tlte i."rpour" Evahmtion Criteria fu Solicl Tturrors TRECIST) Conuuitlee.a:
Chalges i1 only the largest cliarueter (ruridinreusioual nreastu'eruettt) of the tturtor lesions are qse{ in tfie R-LCIST criteria. Nr:te: Lesious ale either rneasrrable ol non-llleastuable using the criteria providecl lrelow. The tenn "evahrable" iu rcterence to l]reasurabilit-v rvill not be trsed because it does nol provide adclitional rtteartilts ol acctuac)'-
untitled h1
9.1 ieasurable disease

lr,leasruable lesiors are defuied as lhose that cau be accruately nteastued in at least one dimelsiol (lolgest cliauretel to be recorded) as l?0 rruu tvith converttional tecluriques (C'T.  
lvfRl. x-ray) or as >10 nurt rvith spiral CT scan. All turrror uleaslueme[ts mtxl be recordecl in gdlgglg5 (or decirnal tractiorts of ceutimeters).
untitled h1
9.2 non-x{easurable disetse

All other lesiols {or sites of disease). inclurliug sutall lesious (lorrgest diarueter "';20 nuu rvith colveutioual tecluiques or.,:10 nuu usiug spiral C'T scan). are cr-rusidered rron-measruable disease. Bone lesions. leptorueningeal disease. ascites. pleural/pericardial elh15ious. lynpharrgit'. .,r115,ipuhuouis. iuflanuuatotv breast clisease. abdourinal ulasses  
  
(1ot ficrllorved by CT or IvIRI). and cystic lesious are all rron-rneasru'atrle.
untitled h1
9.3 target lesions

All rueasurable lesions up to a ma.rinxrm of frve lesions per orgatr aud l0 lesiotts in total.  
representalir.e of all involved olgans. rvill be iderrtitied as target lesiotts and recordecl and greasured at baseline. Target lesic,ns rvill be selected c|r the basis of their size (lesio0s rvith t6e longest cliarneter) and theu suitabilit-v fr:r acctu'ate repeatecl tueasut'erlent's {either by irnaging tecluiques r:r clinically). A sunr of the lorrgest diameter (LD) fior all target lesiors rvill be calculatecl and leported-as the baseliue sum LD. The baseliue suln LD will be used as refereuce $y. rvhicfi to clraraclerize the objective ttruror re$poll$e. There ruay be occasious whel progtessive tlisease is su-spected brtt catutr:t be firlly characterized. Iir these cases tfie trenting pliysician may decide to continue treatrueut for orre or two cycles betbre reassessulert. it'-6e1she tbels it is il the patiert's trest interest and the patie0t agees to contitttre treatmerlt.
untitled h1
9..{ non-trget lesions

All other lesious (or sites of tlisease) rvill be ideutifieei as non-target lesious arrcl rvill lre recorclecl at baseline. Non{arget lesions incltrcle measruable lesions that exceed the uraxiulutr luntrers per orgarl or total of all involved organs as r'vell a$ Dofl-uleasuable lesiolrs. lv{eastueureirts 9f these lesions are rtot required. but the prBsence or alrsence of each will tre noted tluoughout follorv-trp.  
9.5 Guirlelines for Evaluation of llelsurable Disease All measrreruents rvill be taken aud recorded in uretric notation ttsing a ruler or calipers' All traseline evalmtiols will [:e perforurecl as closely as possible to the begiruriug of treatrneut alcl never more thau 4 rveeks before the lregirurirrg of the treatueot.  
The same rnethocl of assessruerrt anrl tlre sarne teclurique rvill be used rvheuever possible to character:ize each iderrtrfied arr<|re1:orted lesion at baseline ancl chrring tbllorv'up' Irnaging-trased evahniion is prefen'ecl to evaluation by cliuical exaruinaticrn wheu both tnetltods lrave been used to as.sess tlte antiftunor effect of a treatrnenl' 9.5.1 Clinical lesions- C'lurical lesions rvitl otly be considered ureasurable whel} they ar-e superficial (e.g.. skin rrodules aud palpable lyruph nodes). In the case of skin lesions. ilocrurrelti-tiol by color photography. including a utler to estirnate the size of the lesion.  
9.S.2 Chest x-rsy* Lesions on chest x-ray are acceptable as uteastualrle lesions rvltert tley are cleru{y <ief,rrrecl ancl sunouutled by aerated hrng. However. C'T is pret'erable.  
9.5.3 Conr.entional CT rrnd N'[RI- These tecluiques rvill be perfcrtued with cuts of l0 lu,l or less ur slice thickless corrtiglogsll,. Spilal C'T will be pertbmred trsing a 5 uuti coutiguous reconstnrction algoritlun. Tliis applies to tumors c-rf the chest. atrdomen' attd pelvis.  
Phase LI rlial of Letrorot"f on'l s*ot-e'ribtfnm:tJ:'."rl;:iJ:J" Poshneuopattral Worneu u'itlt Hontiorte Receptor-Posrtive Locally 9.5..1 Ultrnsound (tts)- Becarxe ore of the eurlpoints of the study is obiective l'espollse evaluatiou. LIS rvill not be rlsed to rrenslue tumor lesions. US ulig,ht be used, at the cliscretio' of the iuvestigator, to coufitrn tlie cornplete disappesrallce of superticial lesious assessed b-v clirucal examination' 9.5-6 fumor markers- Turuor rnarkers alone will ttol be usecl tr: assess respouse' Il' marliers are ilitially abol,e the rrpper nonnal liurit. they mllst nonllalze for a patieilt to be cousidered in contplete clinical response' 9.5.7 Cvtology, histolog-r.- Tlrese tecluiques rnay be used to dift'ereutiate trenveert partial ,*rpori*, (PR) arxi coruplek ,.*po,ir., (C:R) if rleces$ary artd detenuirred b-v the iuvestigat6r.  
-l
-A"io*"al confir:nation of the neoplastic origin of any efhrsion that appeals or w.olsells chu^irrg treaturent rvhen the ureosrtrable tumor ltas ruet criteria for respouse or stable disease is uraudatory tr:r differentiate betrveen respoilse or statrle dislase (a1 effirsiol rnav t:e a siile ettct of the treatltent) alcl progressive clisease'
untitled h1
9.6 response criteria

| 9.6.1 Evrrluation ofT                                                                                                                            | slons                                                                                                                                                               |
|--------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| C'omplete ResPonse (CBtr                                                                                                                         | Disaupearattce of all target leqgg                                                                                                                                  |
| Parlial Resporrse { PR):                                                                                                                         | At t-.tt " 30'n .t.crease in tlte sttut of the longest clia[reter (LD) of target lesious. taking as retereilce the                                                  |
| Le                                                                                                                                               |                                                                                                                                                                     |
| Proqressive Disease iPD) :                                                                                                                       | f ilre tn of target                                                                                                                                                 |
| lesions. taking as refereuce tlte sutnllest sttttt LD recordecl sirrcl the lreattnenl started or the appenrance of one 0r rr]ore lle\Y lesiotts. |                                                                                                                                                                     |
| Stable Disease (SDJ:                                                                                                                             | N.itt**.*acieut sluinkage to quali$' tbr PR nor sufllcient i[crease to qualiti tbr PD. tak[rg as retet'etrce the srnirllest stun Lf) sirtce the trealmertt statled' |
| 9.6.2 Evalustion of )ion-T*                                                                                                                      | Lesions                                                                                                                                                             |
| Dffirc-                                                                                                                                          | "f,rll non-target lesiorls artcl                                                                                                                                    |
| *nor:ualization of ntrrlor tttatker 1.04.--                                                                                                      |                                                                                                                                                                     |
| C'outplete Respolse (CRJ :                                                                                                                       | PilCC*-.far* * rrtot* ,iorr-target lesion(s) and/or                                                                                                                 |
| hrcotnplele ResPottst'i                                                                                                                          | ruairrtenalce of hunor malker level above the nonual                                                                                                                |
| Stable Disease (SD):                                                                                                                             | lirnits. Apl**r*e;tot "  ,ri.ot,i.'ocal pros1'essiort of existing no*-ta'get lesions'                                                                               |
| Progressive Disease (PDJ :                                                                                                                       | ot lllole new lesions ancl'or Y is esceptiottal' iu such                                                                                                            |
| circumitarces tlie opinio' r.rf the iuvestigato. ivill p'evail" per nor:nal lirttit' tltey rnust ruonualize lol a patieirt to lre clllsldeled in |                                                                                                                                                                     |  
Protocol Versiotr: l8jlg-U
9.6.3 Evaluation of Best Overall Response The besr err,erall r.rpour. is the Lest resporise recorded frr:ur the start 0f the treatlrent turtil cliseiise progressi6ttrrectllrellc€ (takirrg as reference tbr prognessive clisease tlte smallest measrueulents 1ecolded silce the treatment stal'ted)' The patienl,s besl resporrse assigrmtenl rvill depetcl ott lhe actltievernetrt r:f bo{r irr*o.,tt*or"nt atld continuation criteda'  
| Target Lesiotts         | Nort-Target Lesions   | New Lesious   | Overall ResPoltse   |
|-------------------------|-----------------------|---------------|---------------------|
| No                      | CR                    |               |                     |
| C'R                     | CR                    | PR            |                     |
| hrcoruplete responselSD | No                    |               |                     |
| C'R                     | Non-PD                | No            | PR                  |
| PR                      | No                    | SD            |                     |
| SD                      | Non-PD .tuiy          | Yes or No     | PD                  |
| PD                      | PD                    |               |                     |
| tur)'                   | Yes                   |               |                     |
| Pt)                     | Yes or No             |               |                     |
| An1'                    | Atty                  | PD            |                     |  
Notes:
patie'ts wit; a global cleterioratiou of healtlt stattr recpririug discontirrualio[ of treahuent rvithoi objecrive eviclence of clisease progressiort at that tifire sliould be classifiecl ,,, lruoirrg"'slruptomatic deterioratio*"' Ever-V effort will tre urade to
<locrmtent the otrjective progressiol' hr so*re cir.cruustances. it uiny be difficult to distinpnrish residual drsease fi'our uonual tissue. \trLen the evaluation of cotDplete response depe[ds- oil this detenniuation, the resiclual lesion will be inr.estigated (tine rreeclle aspirate/triopsy if possible) before conirmilng the coruplete response statrn'
untitled h1
9.7 confirmltory measurement/duration of respone

To be assigpred a stahts r:rf PR
confinued b,v repeat assessmeuts the ctiteria tbr^resporne are lirslat a utiriurur4!{9rva[ rmrst ltave rnet tlte SQff{9I8.-31 r:r CR. cltanges itt hturor lneasuremeuts mtnt be that rvill be perforrned uo less thart itr *'eeks after ulel. tn the case oi SD' tbllolv-up r[easttretuertts of not less tltan I rveeks.  
leasl ortce aftel sflld 9.7 "2 Dur:rtion of Overdl ResPonse  
  
The cLu.ttiog of overall response is ,neasurecl frour the titue ureasttrement criteria are
*ret for CR or. pR (rvhichever is first recorded) unril the first date that recturertt or prog,es,ir,"cllseaseisobjectivel},docuuretrte<l(takirrgasrel.ererrcetbrprogressive
.{tsease tlte srtrallest ,rr*.r,rr'*1rr*tlls recprcled shtce lhe tt'eatrtlent startetl)'
The chrration of r:r,erall CtR is rueasurecl fiorn the time measuretuent criteria are tjrst rrret for CR rurtil the first date that recurent disease is objecti','el.v docuurerrted.  
9.7.3 Duration of Stlblc Disesse Stable disease is rneastrecl florn the start progressittu are uret. taking as refererrce the the treaturent stnfied.  
of the treaturert until the criteria for srnallesl [lea$rueu]ents recorded siuce 10. Removal of Pstients from study/Off Study Criterir 3 u,til one In the abserrce of treatment clelays due to adverse events. treaturetrt ma-v couttnut of the follorving criteria applies:
a) Disease progressiorrlrelapse dtrrirrg active treatment' bj Intercruient illuess that prevents fi.u1her admirri.stratiott of tteatutent' c) Unacceptable adverse event(s).  
d) hr the evept of a1y clnrgr-relatecl life-tlu'eateuing toxicity or latrorato$ abnonnality the patieut rvill be lvithdrarvtl troru turther treatureut' e) Patieut clecides to withdrarv tloru the snrdy' 0 Norrcr:urplialce with trea[nent plart' g) Geperal or specit-rc changes iri tire patierrt's conclition render the patienl tumcceptable for fruther treahneflt in the judgruent of the im,estigator. or h) protocol yiolatiol - auy patieni touuA to have entered this sftrdy iu violation of the protqcol ruight be discoltinuecl fi'om the study at the discretion oi the Priucipal Investigator"
untitled h1
1 1. laboratory evalultions and

11.1 Tissue bioPsies ll.l.t I11 patielts rvith disease thal can be safely biopsied. all atteulpt will be utade to gbtail tissue belbre the start of treatnrent and priol tr: fhe stafi ot'C-vcle ?' At ti[re of biopsy. an attempt will be ruacle to remove tlte equivalent of two cores or r*,o fuu.ti biopsies. ihe tirst biopsy is to be tbr:ualin-t-rxed aud parat'tinerlbeclcle<i. T5e secoucl saurple arrd other adclitioual cores if obtaiued are to be tlash,t1ozen using liquicl ritrogen ancl tltert stored at -70"C to -80"C tor ftlture shrdies (see Study Operatiorm Malual)'
1 l. 1.2 For patients who are registered at attiliate sites. patients will be giverr the option of traveling tr: The Cancer Instinrte of New Jersev to have a tuuor biopsy perfolnerl a1<llor comelative blood studies drawn. Patients tllay opt not to ltave lhese studies drue reurain on tlte shrch" These tests can only lre pertornretl at the the thent
. As statecl. patients tnay choose to corlle to ancl have these tests perir:nned at tio cost t0  
It.l.3 Bigpsies ivill tre obtainetl only if they'can be perfomred under local auestltesia" Ge*eral a,esthesia rvill nor be used to obtaiu biopsies fhat are to be rued only for
'esear.c1 ppqloses. These biopsies uray be otrtained w'ith the assistnrtce of either a sru.gicai colspltaut or 11 ,rr"rrit *r r:f the intervetltioual rat{iology staff' ll.l.4 Bi0psies pertbnrre<l for research purposes ivill-orrl-V be obtained atler the proce,iure'has been explairied to tle patieDt and infonnerl conser{ has been seclre.l per iustitr"rtion policy. Patielts will have the oppr:rhurity to consent or reftne the 6se qf their hrruor samples for arklitional rutplarured studies' I 1.2 ImmunohistochemistrY An:rlysis 11.?.1 Ttu*or ti*.ir" saruples ih.,n, tirue of .riginal 6iag,osis .r it'n.t available' nleta$tatic diaguosis. or if collectecl ou snrdy) will be collectecl tbr each patient on-srudy to e\,alttate the expressiol of L{APK. p}rospfiorylated N{q'PK' \TEGFR-2. plosi:horl la tecl \,'EGFR ::, ancl Ki 6 7 by irrunturohi stoc ltemistr-v.  
l L2.2 Palaftjn blocks containing ernbeddecl tissue samples are pret'ered: horvever if a pnralfirr trlock is rlot a\.allable l0 unstaine<l slicles shtiulti be sub:,ii1-i..3^1.  
Tar CiO Jtrlie Friedruan at the Repositon' Setvice ( BRS).  
Biospeciutett
11.3 Circulating Tumor Cells hr several sftrdies it has been shown that cu'culatiug tumor cetls (CTC's) can be tburd in the p.rrpfr.*f blqr:d of iatieuts rvith a r,,ariet-V of metaitatic carcinouras. Tlte plesence of CTCs lms beerr associate6 with poor plogtrrosis iu patients rvith rnelaslatic breast car:cer.a6 artd si,rilar cglcllsiorrs are likel-v rnre i,:r other rlpes of carcittotuas. Receul sludies lmve alscr rde,ti;ecl trotl the prog.nosri; and preclictir.. ,iiltity tbr detenniniug the mtmbet' of crcs in patieuts rvith uetastatic Lrreast .ou.*r.t''o' In additiou to qtraltitatiilg C'TCs, these cells Dtay provide al] opporflurlty to characterize ruolecrtlar changes irr the tlm]or" thereby helplrg to iuirle target"d *r.rupy. i' this shrcl1.. arral;-sis of clta,ges in tle ttttmber of CTCs' pre-treatr,errt aurl atter i "i,.t.* ,.rf treatrrieut. .ui1 be pertbnrred_anil cornpar^ed to radiological sfuclies 6lrtaipecl at siliilar tirue points. Detnils regalding collection. handling. storage' artd shil:piug of bloocl saruples ivill be provicletl in the Strrdy Operatiotts ltl'tanttal'
untitled h1
1i..1 imaging studies

The potenrioi ''oi. of clvuarnic coulrasl-euhancecl coutptttecl tr:urog'aph-v- r:r perfirsio[ CT
(pC'T) in rponitoring tieatnrent ,,vitb artticancer og"t t* tlrat aftect trurlor angiogertesis is
*o.olvirrg. pcT is a
-rrorr-irrva*ive firnctional irnaging teclurique capable of assessitig nuilor ruicrovasc.lah*e "rir*"riv.-l The pcr tecluriqui is based oir the coutinuous acquisitiorr of 3D CT images durilg the clistribuiion of an iutravenously adrrlinistered iodirrated contrast il,ti:.lllilil" f r;,:"ilr.:H J:'il.H f ;Im,*:fi: ?[.,ff :lfl i" Po s"ne'o,a"sar nr,f agent bolus. The coulrasl agenl is FDA-approvecl aud is ttsed itt t'otrlitte clirilcal practice.  
T[e total contlasl athrinistered to each patient is witliil the FDA-approved limits.  
Perfirsic,n C'T does ntrt ilrr,olve the nse of au iltvestigational der,ice.  
11 this studv. pC'T tvill be pertomred before trefltmellt ancl after t"ivo cycles of treatrttettt in t;l*:u*:;l;*:*:ni::r.':.l;,r:tru;:::::::x,n,m nuuor. All pCT exauriuations will be perfonuecl ou tlte dual-sotuce Siemens Souratottt Definition C'T. pC'T rvill t:e pertirmred 5 rnimrtes folloting the acr'prisitiort of the stanclaldot'-care coltrast-enharrcecl C'T. The pCT ivill be acquiled follor.ving au additional infection ol "10 nrl ol iorlinatecl cr:ltrasl al a rale ol4 url,'sec. -Ihe clytl"rrrt* acqtrisitiorr rvill take plau-e at 6 tirne poiuts at 3 seconcl intelals tblloiving tlte contt'asl ir{ectir:n. Each inrage acquisitiorr rvrll consist r:f 6 slices of 5-nut thickness. Ilttages will lre tt'alsl'ened to a scientitjc rvorlistatiou for analysis using the DICO\'I protocol. Blood tlorv to the lesion w'ill be measurecl using the nraxiunuu-slope maclel. l\,{eastu'etueut of tlte blood tlo'uv r.vill iuclude rutanual segureulatron 1o exclutle large blootl vessels ti'orn the region of illerest' Due to resoruce constraints. pertusion C'T $CT1 testiug w'ill nol tre lterfcrnned ott an-Y
parierrt in the strdl'. As of 0lr2i.i:013 pelfusion CT (pC'Tl testing ltas beett t'euoved ti'onr tlte study evaltratiotts tat:rle (see Sectiriu 6),
1f .5 Optional antl Future Studies (onlV for Cancer Institute of Nen' Jerse.v patients)
ll,5.lAllshlti,vparticiparrtsatthervillLreirrvitetltt.l pro',,ide a bloocl saruple f@lig. Participatiou in phannacog,enetic shrclies ivill tre optional fol all palients ettterittg the shrdv. A
patienl's acceptauce olphanuircogeuetic annlyses rvill nr:t be a t'etluileurertl of their participation in the urail shtd-v. See Stucly Operations lt{anual firr details of sarnple Iabeliug. collectir:rt. trutsport. aud slotage.  
I1.5.? AII snrdy parlicipalts at tlte rvill be invited lo prclvitleabloodsautpIetbrhrtlrxeutartdaftertrvo c--r.cles of treRtrnent. Participatiou rvill Lre optional tbr all pafieuts entering the snrdy^
A patient's acceptarlce of turplarurect trrttue analyses rvill not be a requireurent of their participatiorr il the main study. Patients rvill have the olrportrnity to consent or refirse the tne of these samples t'or arlditi,rrtal rurl:lantted sftrclies. See Snrdy Operatiors lr.lauual tirr cletails of sample labeling. collection. trarlsporl. and str:raqe.
untitled h1
i 1.1 shipping instructions

All saruples are to be ideutitied s assipred registrati,tn rrrurtber an<l shipped rvith refereuce to Breasl sftrdv Slieles ancl Tissue blocks at'e to be seut t:
ovemight express to tlte
(BRs).  
ii[::":i.Ii]i1;j,TJ""i:f"mL'.Tr,.l}.H,}m:?::..-I,i::1r:i,,Postttrettopatrial ,,.8
untitled h1
paraflin blocks

Please wrap palaffiu bloeks iu bubble writp or soure rnaterial that rvill cushiort thetr. During spriug aut{ sruruuer rnonths paratliu bk-rcks must be shipped with a cooler pack insicle the shipping container or ttre ivax rvill melt and tlte specinterr rvill be cornprcrruised.
untitled h1
ghss slides

Glass shdes rnusr be urailedlshippecl iu appropriate protective slide containers. Tltese cau tre rlatie of carclboarcl (flat slide holcler) or plastic (slicle lrox or slide shipper).
untitled h1
documentation

Please har.e the narrle. acldless and the appropriale latroratot-'- or oftice phone rturnber of lhe institution thnt the patient speclluells wel'e shipped ti'oru. For aly qttestiotts relating to shipruent of sautples please call
untitled h1
12. pharmnceuticnl information 1?.i sorafentul

Name: Sorafenib. Soral'enib tosvlate is the tos-vlate salt of soratbnit: I -  
  
rilTT- t 3 -(.1-chl olo -3 - trillrtolonretltvl-piiffiro].pherr.:x1.}-prrlcline-].7.arboxr,licacidrrreth,vlarrride.1meth-Vltrenzettsttlfottate attcl its ntolecular fonmrla ls Ct:HreC'IF:N+OrXCrHno-iS. Molecular rveight of soralbnitr (tree base) is 465 Daltons attd st'rt'aferrib tosylate is 637 Daltons' How Supplied: BAY .13-9006 sorafenib 200 nrg is strpplied as rounci, bicouvex. red-tilur-coated tal'llets, debosseci rvith the 'Bayer cross' ott one srde atd '200' ott tfie otfier side. The tablets contain BAY 43-9006 tosvlate equivalent to 200 grg of the free base BAY 43-9006. ancl the excipiertts croscamtellose sodirun, rnicroc,r-ystallile cellulnse. hlprornellose. sodiurn lau'yl sulfate. and rurag&esiuur stealate. The tlhu-coat consists of hlpromellose. polyethylene glycol. (itaniuur clio.ride aucl red iron oxide. The tikn coatirtg has no effect on ihe rate of release r:f the active BAY 43-9006 tosylate.a6 Sorafenib rvill not tre provided ald is cornmercially available. Patierrts will be given assi.stauce olt lrorv to obtain sorafeuib. Patients rrray lmve to pay tbr it or be respqusible for sry co-pa.vs associated rvith ol:taiuing rlnrg supply.  
  
i,l:::.lllliiil"rL-r'"i:r.:HirJi::fi f ilIF.",n:fi:?i:.I'i::1$"Post,re,opaurar O',7 Storage requirementsl Stabilitl.: Tablets are slable al roortt temper:attue. Do not  
  
store above 35*C (7?*F). Store irr the original package.. Tlte curent shelf life is 36 ruonths.  
Route of aclministration: The dose of soralbnib to be taketr by patients rvill [:e cleter:linecl t)'our the phase I conrponertt of the trial. Soraferlib is available irr ilulecliate-r'elease preparations and thrm the active irrgledient is cortrpletely dissolved in a shorl penorl of tinie atter oral adttriuistratir:u of fihn-coatecl tablets. Sorafenib should be taken on an eurpty stonrach" at least I hour befr:re r:rr 2 hr:urs after a ueal.  
Tablets should be srvallorved rvhole, uot cnrshed ot'cherved. 'uvith 8 olulces or 150 ml oi rva{er. Il shoulcl not tre ta}ien rvith grapeiiuit juice.a6  
| Expected toxicities: Ach'erse Drug Renctions in patientr in multiple clinicrl trills I'IedDR{ cotled System Org:rn Class Verl'Cornmon Conrmon I-rncomnton > 0.1Yo to < lo/a > 100/0 > 19,6 to < l0Yo Irt'ectiorn aud Folliculitis urt'ectiort infestations Blood artd lltupltaric L.r.nrphopeuta Leucopenia Neutroperda syslenl disorders Aneuria TluourbocEoperua Hlpersensitivity lnuntue syslem disorders reactiotts iincluding skrtt reactions aud tuticaria) Erdocrfute disorders Hr,uothyroitlisnt Nletal:olisur aud H-rpopltosplmtelda Anorexia Hlponatrertua Dehr,clratiou mrtrition clisortlers Psychiauic clisorders Detrressiori Peripheral sensory/ Reversible posterior Neryous sysleln disorders neruopatltv leukoeucephalopathv* Ear zud laby'irttlt Tiurirus disnrclers C'ardiac disortlers N.{yr-'rarclia I ischettda and irfalctiout Congestive ltezu't failure* \,'ascular clisolders Hernonlmge (including gastrointestinal* and resptratory, tract* atttl cerebral heurorrlmge *) H\.?erlettsir-rtt HJpetensive ctisis* Hoarseitess Rltiuonltea Respilatory. thoracic ancl urediastiual disortlers Gastroiutrstinal Diarrhea Coustipatiott Gaslro esoplmgea slo ttts_Iir (i$Iditg. sE reflux disease disr:rders Nausea Plolocol \ier:iotr: 7, 6,'lQ1,1 I-16-   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
i,ll#;lili:il"''"*il:"-Hilt::ilfil.ilHt*:?::',1t:1,1';i"Posh':re,opa'l*ar O',7  
| Slstenr Orgln C'l:rst                                                          | Yerr'('ommon                                                                         | Common                                                                                      | flncommon                          |
|--------------------------------------------------------------------------------|--------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------|------------------------------------|
| > l0o/o                                                                        | > lo/o to < l0o/o                                                                    | > A.Lo/o to < l7o                                                                           |                                    |
| Vondting                                                                       | rurouth aud glossodlteal Dyspepsia Dysuhaeia                                         | Palcreatitis Gastritis Ciastrointestinal perforaliorr*                                      |                                    |
| Hepato-biliary                                                                 | hrcrease iu bilfurrbin artl                                                          |                                                                                             |                                    |
| disorders                                                                      | iatutdice                                                                            |                                                                                             |                                    |
| Skh and subcutaneous                                                           | Rash                                                                                 |                                                                                             |                                    |
| rissue disorders                                                               | Alopecia Hand-foot reaction** huritis Entltema                                       | Dry skirr Denuatitis exfoliative Acue SI':n desquarnflfion                                  | Eczenra Erlthema uultifomre nilnor |
| It{usculoskeletal. corurective tissue ald boue disolden                        | tullualgia r"Il,algia                                                                |                                                                                             |                                    |
| Reproductirue s.ystelrr                                                        | Erectile clyrtiurction                                                               | Grnaeconraslia                                                                              |                                    |
| aurl breast disorclers General clisorclers aud adrunistratiou site conrlitious | Fatigue Paur {inc. nrouth. abdourirral. troue palr. headache ancltrmror pain)        | Astlrerila Fever Lrfluenza-like illness                                                     |                                    |
| Investigations                                                                 | Lrcrea:erl amylase                                                                   | lVeiglu decreasecl                                                                          |                                    |
| Increased lqrase                                                               | Trausieuf ilrcrease trarxaufrtases                                                   | Transient Lrcrease in blood alkaliue phosphatase LNR abronnal. protlu'ourbir levrl abnomral |                                    |
| *                                                                              | Everrts may lmve a life-tlu'eaterriug or tatal outcorne. Such events are rmcolluuorl |                                                                                             |                                    |
| ** Palual plantar erltluodvsaethesia sl.ndroure ur N,IedDL{                    |                                                                                      |                                                                                             |                                    |  
Lt cottbinafion rvitlt cllotoxic agelrts^ nr1.'elosrpplessiou leadiug to l.ebrile ueulropenia lms also been obserued. Such events mav have a life-tlueatenins or ihtal outcoure.  
Drug Inter*ctions: Based on uuulerorls Plrase i osidati'l,e aud Phase II
qlucnrouidaliou nretat:olic pathivav in vitlo trials. the potenlial of sorateuib to intemcl rvith other dnrgs is lorv. f'he soraterilr tosl'late is rnetabolized by the CYP P450 enzlrratic pnthrvnl,.' (specilicall.v C'YP3AI aud theretbre rra-v interact r.vith other dmgs thnt utilize this pathrvay. Close urouitlrring is suggestecl in patients taking rnedications srtch as rvartarin. carbarnazepine. phenl'toiu- quitidine, phelobarbital. aud digoxin, rvhich are nretabolized b-v the lir.er ancl have srnall therapeulic ranqes. Sorafeuib has been seen to increase levels of cloxonrbicin. docetaxel. nrrd iriur:tecau. but the cliuical iruportance olthese elevatious is ulclear antl cturentll,t:eiug studiecl.ae i,lH:"',1ilili1;,l,f,ri:5*HtJ:nTrlil.m:;::,x*:l::1iJ;"Pos"*e'lropa'rar O',7 l2'2 Letroz'*o;ttlor.zole rvitl be s*ppliecl to patients at ,o cosr r,r- I
I It rvill be supplied as 2.5 rug tablets and one brtttle will coiitnin 30 Efrlt:F.6f. is ar,ailable as a 2.-5 mg dark .vellorv filnr-coated tablet. It is a sytthetic aclriral benzhy<lroltriazole derivative of the chemical narne 4.4'[(lH-1,3.4-triazol-l-yl)rpet[-vle1e]bisbenzonitrile (I.{W ?85.31). The courpoutd ftnnula C17II11Ni is odorless. r.vhite to yellorvrsh crystalline ruaterial. fi'eely soluble in dichlorr:rnethaue.  
slightly soluble in ethanol. artd practicall-v insoltrble itt rvater.  
Storage snd stabilitl: \rery statrle at roofir tenry:erafiue: shelf lit'e is 2 years.  
Route of atlministrltion: Patients lvill take one 2.5 rrg tablet b1' ruottth once a clay.  
Letrozole is rapiclly- absortreti ancl courpletely bioavailal:le af]er c,ral admiltistration of tilur-coated tatrle ts.  
Toxicities: The urost tiequeull.v reporled aclverse evertts rvere lteadaclte. natxea, vorniting, peripheral ederna. hot tlashes. fatigue. hair thiruring. bone pairr. back pain.  
artlua I gia. attd d-1,5p1196.  
Drug internctions: Basecl ou tlvt'r phanuacokinetic clnrg iuleractiott studies (rvarfariu.  
cirneticlirre). rer,ierv of data ti'onr large Pltase tli tlials. atcl lhe in vitro restths r:rt c-\.tocluome Pr150 enz-vutes. (he potential of letrozole to interact with other clnrgs is low.  
No close a<ljustrrrents al'e reconurended nor required fr:r patients r.vith renal or liver impaimteut.
untitled h1
12.3 drug accountability

The ilveitigator is requirecl to nraintain adequate recotris of receipt. clisperrsirrg arld tinal clisposition of stud-v chrrg. This responsitriliry,' has been delegated trt tlte phanuac,v. htclttde on r".Lipt record (e.g. packing slip) flour and to rvhou stud.v dnrg rvas shipped. date, qtlalltity. arld
$atch or lot luurber. On clispensing record. note quanlities atrd dates shrcly tlntg rvas dispeused to and letturted b-v each subjecl.  
12.4 Dru g Destrucfion/Disposrl Eurpty ancl partiall-y enrpty containers of snrd-v dnrg rvill be clisposed r:f in accoldnuce rvith institutional poficies aucl procet{ures. [Jmrsed containers of stud-v dnrg rvill be rehmterl to the sftld-v sporlsol fr:llorvilg corttpletion olthe stttdr'.
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13. dltl collection and records

13.1 trlectronic Case Report Forms The Plat eac[ ilsrimtion rvill be responsible tbr asstuirtg that all ilata specifiecl irr the shtcly-specit'ic tiata capnu'e plau is collecterl altcl entereel onto the electt'ottic case repofi fonils
(eCRFs).  
Phase Llll Tlial of Letrorot.f ancl Sorat-enilrI a: Firsr-Lure Therapy irr Postureuopatrral
\\roruerr uith Horrrroue Receptor:-Poiiiire Locrlll'Adr':rnced or \leta"tatic Breast ('attcet' ,,,I
l)ala subruission guitlelrnes are ur concordaucri with those expectecl by the National Cancer Instihrte. i.e.: Baseliue data is to be elltererl outo e('RFs rvithiu 2 w'eeks of initiation of treahuent. Sulrsequent eC'Rfs Are to be eompleted rvithiu 2 weeks r:f the clate iu which the previous cvcle ruas cr)ruDleted. All e-CRFs rvill be suburittect to the OHRS al the lits st'cru'e rveb-basecl data nranageluent systeur. The e-CRFs are lburul iu the shr<lv specitlc crlendar tlrrl has been crealed in the dala urana"eeulent svstenl.  
The s-v-stern rvill proupt the user to the tbrurs thaf are requirecl basecl upon the patient's eru'ollment ancl tleaturenl tla(es.  
Perioclicall]'. rnonitcring antl,'or aucliting visits rvill be cou<hrcte<l b,v the f Irttorti161i11g,..atrditirrgstalrtelrllteptlq:r:seofr,eri1yingo*to"iiffi rvith sorirc'e docuurentation. The participatiug instinrtion wrll provide accesii to the patiertt's r-rriginal recorcls tt"r pemrit verificatiou data errtr--v.  
-ia
untitled h1
13.2 research chlrts

A research chart (i.e.. shadolv charl) is urainlilined at OI{RS fbr each patieut eruolled.  
Copies of the most signiticanl shrd-v source docrunents rvill be rnairttained in the lesetrrclt chart. Exaurples of source docunrent copies thnt rvill be rnairtaiued in the research chart irckrcle: signecl ilionued conseut fonu. clocruuents that verifi eligibilit-v and treatrnent and documeuts that i'erit1'Ciracle 3-;l a<lrrerse elents anrl response. This irfbr:uatiou rvill be updaled oil a prospective basis aurl ivill tre conlidenlially uraiutaiued at lhe OI{RS^
untitled h1
13.3 reports

tbr suburission to the IRB and FDA tvill be writtert by tlte PI using tlre data caphu'ecl ou the CRFs. Shrrl-v pro$'ess reporls rvill lre plovided to participating irrstinrtious tor^suburission to local IRBs.
untitled h1
1"{. drts and safeh }ionitoring

N{onitoring of this shrd,v r.vill occru iu accoldance rvith the NC'I approved Data aud Salbt.v Monitoring Plan (DSMP). .fur "initiation audit" wi conclucted try' OI{RS Qualitt' Assruance statf in accordar}ce rvith the DSI\,{P tbllorvilg em'ollureut of the firsf tu,t-r (]) or tluee (-1) patients. Sutrsequeut auclits will occur on an aruttml basis if the finclings trom the initiation nudit rvere satisthctor!'. lr{ore ti'equent audits of Jratient clata ant'l stu<ly coirduct rvill occrr if uece$sary. AllIceuters rvill be monitored it least quarter:I1' and audited uuurnlll'. Prior audit findiugs au(l"or sitrmtious that mav arise dru'ing the cotuse of the stuclv rvill detemrine the need tirr rnole li'equent aucliting. All auclit fiudirtgs rvill be reprrlte<l to the PJ. H,ruan Research Or.elsiglit C'ouirurttee {HRilC'1 ilntl to the I
hrsti tutiona I Revrerv Boarrl
untitled h1
15. multi-institutionnl guidelines 15.1 irb

As the Cr:ordinaturg Center fcrr a trial. it is the coordiuating center's respousibilit_v to ensrre thal no patieuts are entered on the trial at a participating institrrtion witltotrt full IRB
npproval. Thus. OHRS rvill approve the additiou of each participating irrstitutiou to the I I \\'uurerr uith Horrrrorre ne.-ept.riPolirir e LocrII1' Arh1TrEffi[j PI:
study. A copy of the IRB approval docurnelt fi'our each participating irrstilutiorr rvill be obtained prior to acti'vatiou of the stud1, at the parlicipatiug iustitutiorr.
untitled h1
15.2 other pre-study documenfs

Each parttcipaturg center is required to lrave the tbl]orvinq docuneuts on file at the OHRS:
r Curricula Vitae of all physiciarr Investigators o Siguecl FDA fonu 157? of all physician Investigator:s o Rutgers Financial Disclostue of all physician hrvestigators if site is under the Rtrtgers IRB of recr:rd. If a site utilizes theil local IRB, their approval covers this ald rvould not appll'Docunterttatrou of Hurnau Sul:jects P:otectiou trainirrg fi'om all lnvestigators o N{edical license liorn each hrvesricator
untitled h1
i 5.3 initintion site lrisit/s{eeting

A shrdy initiariou nreeting r.vill be condtrcted rvith each parlicipating institution prior to eruolluteut of patients tioru the institution. OHRS staff rvill couchrct the study iuitiation lneeting in close proxirnitl' to IRB approval of the studv at the par"ticipating center'. In mr:st siftmtious the studt iriitiation ureeti.ng rvill tre conclucted via teleconference.
untitled h1
15..1 irb continuing approvals

Lrvestigator^s t}otu parlicipa{iug instituticus musl pror,itle a cop-v of the irntitutir:u's appt'oved cnutimrirtg revierv cloe'ruuentation. Registratiou rvill be halted at any participating irtstifutron in s,hich B cull'ent coutintriug a,nl is not orr tile at OHRS. C'enters who are approved to utilize the Board rvill not be requir:ed lo file conlinuing review lu)]elltatlou
untitled h1
15.5 amentlments nnd clonsents

The OHRS rvill uuiirttnin a colrv of all aurendments. corserrt fcrnus and approvals fi'oru eaclr pnrticipatiue institutiou. Cortseul l'omrs rvill tre revierverl and approved b1, OHRS to ensrue hrsrrftrtional Revierv Board approvecl consellt. Sho@ llle necess{u'}. protocol aurendruents rvrll tre sulrrnitted irr rvlitins to the PI ancl local IRB tbr liest inGrest is endaugered. In that and local IRB rvill tre ntade as sooll as possible cousisteucy ivitlr the appror,al prior to
untitled h1
1 5.6 patient registration

All patients tom participating in.stifirtions rnust register patieuts with the OHRS central registratieu desk. as describet{ in Sectiou 5.7 of this protocol.
untitled h1
15.7 data (lollecfion and toxicitv

The PI at eaclt irrstitrttiorr rvill be respousible tbr nssruing that all the required data is collected aud etttered onto the eCMs accuratelv aucl cr:rmpleted eCRFs submitted as described in Section 13.  
nr'I
15.8 Data llonitoring lntl source Document verification Each sire participatin{in th* accrual of patients to this protocol rvill be auclitecl tr-rr prott-rcol a1,{ regulatorl,'clmpliance. clata veritication nttd soruce cloctuttetltatiott.  
The staff rvill cottdrtct reulote rttottitorirtg on a contiutml t,n.,,.illtttt.rtillorirrgr.isitso.ccturiltga5lleCeSsaI.v,Tlrt.  
nc,uitorigg visiis lvill tbcrs ou verit-ving clata rvith sotrce doctunents. Adherence to tlte proi*"oftrl. inclucling the prourpt reporting of seriotts aclverse e'-ents. rvill be assessed' iirr,lirrgr'of all ruonitoriug visiti o.* ,".ordecl on a il'{r:rritors Report- rvhich is kept in the OinS'repnrlatory file. Issues coucerniug study cotttpliarrce ate reviewed at reg$lar meetiugs r,r'ith tlte I{ROC'.
untitled h1
15.9 dnta nnrl center autlits

.staff rvill condnct aunual audrts to parlicipating ce[ters
$ffiia Operarils Procedru'es (SOPs). T1e aldit ggideliles are accottlaue'e rvith the arrrl Salety lv'lonitorilg Illan irr in
untitled h1
16. stltistical consitlerations

16,l PrimarY rnd Secondnry Hypotheses Tle study rvill require a short nui-in phase I porlion to detenuine the recoru}ettded phase II
close. I lie prilrary objective of the single airu single-stage phase lI pr:rtiol of the stiltly is to detenuiue the cliJical Lreuet'rt rate (proportiou of patients rvho aclieve a contplete r.esporse. partial respoose. or stable t{isease .l 6 months) of letrozole and sorafenib as tirst-lin. ttrerapy i1postsreuopausal rvorleu rvilh homrone recelrtor-positive locally advaflced or uretastatic breaxt caucer'. TIte seconslarl objectives ale to detenuitle the satety ancl tolerabilit,v of sorat'enitr in courbilation rviih leti'ozr:le and evitluate titrre to progression artcl overall stu't.ival.  
16.2 Sample Size Justification A list6rical stlcly showecl that single-agenl letrozole in the t-rrst-line treatrue[t of patieuts rvith Sonnone l.eceptor-positive ruetastatic breast cancer had a clirrical beDefit rate of 5006 colrparecl to tarnosifenJ Th" courtrination tlierapy of letrozole aud sorafenib lvill not tn consit{ered of tiuther interest if the tnre cliuical trenefit rate is less than or eqtml to 50o'ir. We assurne that tlis sttr{y will target a clinical lrenefit rate of 6796 for identil-ving the courtrilatiog ttrerap-v as active and rvorth.v of fiuther irrvestigatiern. With tlres-e settittgs' the ulll l1,pot5esis is iliot ttre clinical benefit rate t"rf tlte cr:urbirtatiou therapy is less thau or equal io 50o.'o. ancl the altenrative h1,.pothesis is that tlre clinical trenefit rate of 67orb or tnore is of consideratrle iuterest. For lhe phase II part of the shrcly. the sauple size rvns calculated accorclilg to a single-stage desigtr.4' Tlr. study will accrue a total ol58 patiertts. and the combipatiol rherapyr.vilibe accqrte<lif there are at least 35 responders ottt of 5B patients' T5e design rvill Sare a 4.30'o 1": 5oo) t-vpe-I en'or (talse positive) rate and a power of 82'7,qi'
(> Bgo,i,') (i.e.. 17.3o,.'o type-Il error or fhise rregative rate). Tlie total ttrunber of evaluable patiellts to be accntecl to tliis shrcl;- is nol expected to exceed 6'l patieuts' l}:::"''Jl'Ii,i1;j}j}."il::mt;-.Hr,im,:;::,*?::-,xilxffi,,Postrtrerropalrral N',7 The patierrrs accmecl iu lhe Phase I dose escalatir:n rvill Lre iucluded irr tlre Phase II portion if they receir.e the sarue dose. Erraluatrle patients for the phase I portion are clefiuecl as study-g1ldble patients who have receivecl nt least one c-vcle of treatniettt. Evaluable patients for the phase II portiou are those rvho have receivecl at least tr.vo c1'cles of treatrnent'
untitled h1
16.3 outcome }lesures

patients ivill be evahmtecl based on clinical lrenetit rnte. ffs descril"red in Sectiorrs 6 ancl Section 7. The rate of clinical benefit is detinecl as the proportiou of patieilts who achieve a conplete response, partial response, or stable disease .:r 6 *ottrrr*. Tiure to progressio[ rvill be calculated based ou rhe tirne behveen the first day of tleatmeut afld the date of disease proguessieu. Overall sunival ivill l.re calculalecl Lrasecl cu lhe tirue tretrveetr lhe hrsl day of treatruent and the date of cleath ti'r:m anY cnuse.
untitled h1
16.-l analysis

Tirne to progression antl overall srur,ival rvill be suuunalized using the standard Kaplanlvteier lritlocl. Ihe l}equeucv ol'serious adverse evenls as oullittecl irr Sectiou 8 rvill be descrttred b-v* s6uuuarl, sfatistics. Biological eud poiuts obtained trorn biopsl'specit[efls are likely to be assessed semi-quantitativel,v*. arrd courpared ttsittg ttottparatnett'ic methc'ds to detenuine ccrnelatiots rvith fturtor response and tlisease ptogression.
untitled h1
17. human subjects 17.1 subject

posturerropagsal rvorueg rvith previousll' ruttreated ltotrttotte leceptor-positive locally advance<l or uretastaric trrcast calrcer uray padicipate iu this tlial if they nteet the eligibility criteriil. The ilclusic'r1 alcl exclusir-ru criteria clelailecl in lhis prolocol are clesiEred to exclttclepatiell1lst.rlel-vtbr.rrleclicalrenslatiettts*.hrrate receivitg care for their disease at the 0rarI
a t'fi lia ted uredrcal oucolo gv pra c tic es andEoirurnuri 11' and OHRS lesearch persounel rvill closel-v ntouitor the stanrs of tlre strrd,v (and iridividual patielt clata) at all ceuters. lr,{ales tvill uot be eligible lbr this studl'. Breast cal}cer irr ruen is rare and the etlicac.v of aromatase inliibitors itl males is liurited.
untitled h1
17.2 potential risks

All care rvill be taken to ruiniruize sicle effetts. hut thel.can be urrpredictable iu ttahtre ancl severity. Reported sicle etlbcts of letrozole inchrrle headache. nattsea. r'orttitirtg. periplreral ederla. hr:t i'las[es, fatigpe. hair t]rirutirrg. b,rne paiu. back pain. artlualgia. aDcl dyspnea.  
i"-{ost of these side ett'ecis thal rvere observecl iu patients rvho t'eceived letrozole in cliuical snrdres wel'e llot ccrlsiclelecl serious ancl were geuerally ruild to moderate' Repor-ted side effects of sorat'enitr ilcfurde hancl-fool slrtclt'oure. diantea. fatigtre. hyrettelsiou. pain aud rash a1d were uoted to lre maiuly rrrilct tt'r rnoclerate. Grade 3 and 4 reaction$ rvere rtr:ted tt:
be uncoluuol arrtl $eell as elevations in selutn amylase and lipase levels (lvith corresponcliug s!1ilpto1ts of pancreatitis) artd hagcl-fbot slr1drotue.ae This snrcl.v nrat, iuvoh,r' risks ro patientx thal ale crurentlv rutforeseeable" Patients eru^olled irr tSis triat iviit receive t|eir treatmeut in au outpatient settilg. hr additirx, r[c,nthl1"blood wor"[ rvill be takeu to urolitor sicle effects. Er:aluations at each cycle to ruolitor tlte treatureut of patieuts r.vrll be pertbmrecl and recotded in the palient char1. For patients at the 1 T:: ll' ji,x';,l :[:- J::;I"\#ffi l:;:]'[
":fi ffi J"il:
cogrplications arrcl to iurprove long tenu care. Alihough no cotnpensatiort is available- any irqur] g,ill be evahmtecl aucl treatecl in keeping rvith the benefits or care tc"r rvhich patients are entitled turder applicable regtrlatiols.
untitled h1
17.3 consent procedures

lntbglecl copsellt unst be otrtained plior to conunettcittg illlY research procedures. Tlte PI
shall seek such colserX o1l-v'turcler such circtutstallces that provide the prospective patieut opportulit-v 1o cousider r.vhether ol'llot to participate artrl that nr.urirnizes the possitrilit.v of coerciol o1 rur,Jle inllueuce. Tire intbnnaliotr given to the J:atieut. or tlte reprcselltative, strall be in a lalguage uurlerstauclalrle to lhe patienl t)l l'epl'esentalive. 'I'he irtlbrrued consent
{ocruleut uta1. not inclucle any excttlpatoly langttage tlu'ough rvhich the patient or representative is tuat-le to rvaive any of the patieut's legal riglils or releases. or appears to release the urvestigator. the sporlsor or tlte furstitutiou tloru liability lbr negligeuce.  
The iuvestigatiorral uature arrd ot{ectives ol this trial. the procecltues attd treatrneuls irrvolvecl arxl t6ei1 a6eldaut risks. discorutbrts, and poterrtial treuetits lvill be carefi'rlly explainecl fo the patient. This process rvill inclucte a getteral <lescription of the clisease 1rro"..r. as rvell as a clescription of the patient's espected cliuical cotlrse. AltentatiYe ilerapies q,ill be tirllv descritiecl. auct ourlined iu the conseut clocuutent. The patient rvill be asketi to r.eacl the coitseut al his,her^ couvenieuce ancl rvill lre ertct"ruraged tr.r ask qttestiotts.  
Enr.ollmegt o1 this snuly rvill onl1.' occru if the patient meets all eligibilitl" criteria. is judgecl bv the Prilcipal hrvestigator or parricipaliug investigator to poteutiallv benefit fi'oru the ttierapl,'. is u,illing to pror.ide consent. aud has signecl tlte consent clocturteut. Nloreover. atty espeiiinerrtal ilr'asive plt'rcerhue rvill reqrrire a separate cotlsetlt for:n (staudard proce<ltre c0tlient lbflrr).
untitled h1
17.{ potentirrl benelits

It is likely that a si$rillcarrt proportion of patierrts rvho participate in this clinical trial w'ill receive <lirect clinical l:erretit Lrecause they ivill be receiving a dnrg that is comutouly tnecl tbr tleir.disease. fhis benefir rnay be reductiorr in the size of theil fu[rot. stabilit-v irr the srze 6f their hunor'. aucl'or implovernent iu s1'ntptoms t'elated to their disease.  
As a resuii of partrcipatilg rn ttris tri{.1{!1gqp1;ill receive erraluaticrtt artd treatntertt of tlteirfi.urtoro''l,;_oralllteerrrollirrg.Ialfiliatecl irrstitrr1iorr..rhe*r:le.rvillbeprovidedatnocItar.geto eruolletl patielts. Hoi"ever. arlctitional medical sen,ices rvill be billed to the patients ancl'ior their irrsruance carriers il} the custoluiuv wa\,. The cQst 0f conelative phanuac0dlrtauic sftrdies rvill not be billed to the patrent or ittsttrer.  
il,fi:1Xf;'ii;iff ["i:[ffi :t;'.Hf l].iltil]:fi:*..I'[:1,t;"Pos'1r':re,.'a"sar nt,E
untitled h1
i 7.5 risk-benefit rntio

The poteutial benet-rt that may result tronr this sfucly balauces tlie potential risks to the patieuts. A urulticenter Phase III tLial iuclicates thnt letrozole is superior in etficac-v to tamoxifen tn the tirst-line treatrueut of postmenoparnal wouleo rvith honnone receptr:rt'-
pnsitive uretastatir: breast .olr.et'.* Hower,er. it is not ciear lrrhe(lter tlte courbination of letrozole aud sorateljb is supelior to letrozole aloue. lrul the tlteoretical approach of targeting fti,o pathrvays of tuuor progressir:n simultaueously is ertcouragiug. This protocol urali or nra,v uot be helpful to a specific patient. but the results ruay help tlte itn'estigalors lear:r atrout the achrruistlrrtion antl ettectiveliess of letrozole and sorafettib in lrreast carlcer ancl nray aicl in the treatureut of otlrel patielts. This research treatrueut is uot ctrratil'e. btrt ma1, oll'er lernporary coutlol of the disease. Benetlt carurot be prouti.secl llol'call the cltance of lrenetlt be accuratel-v predictecl.
untitled h1
17.6 gender nnd llinorities

The Nalional hrstiftrte of Health and NCl har.e stressed the inrportance of geuder and utinorit-v iuclusiol iu clirrical selices and research. All'ican Aurencans utake up I l9'o-H.isparrics6o,o.attclAsians59oof,h*Etrlatiertts.l.eipectir.el-v' The pelceutage of rtrinoritv J:atieuts eiu:c,lleil onto clinical lesearch ttials were l2o.o Attican-fuirerican. 60o Hispalic. aud Cro.o Asian. r'espectivel)'.  
No person shall ori the gl'orurds of race. color or uatioual origil. tre excludecl ti'our parlicipatiou ilr. be cleniecl the lreuet-rts ol. errollurent in this sftrd-v. There is a restrtctiott regarcling tlie sex of the patlerlt. l\.lintirities are plevalert in the area.
untitled h1
18. economic/finnncial considemtions

Patierrts aud,'or tlreir iusurauce caniels ivill lre expected to pa], for cosls relatetl to utouilolirtg and follolv-rrp. Patieuts will be expected tc) pay tbr any* costs rrr:t paid by their irtstuance carrier. The cost of con'elatir,e snrdies will uot be billecl to the patieut or instuer. Patieuts rvill not be expected to pay tbr the cost of letrozole and sorafenitr.
untitled h1
19. publication of resenrch iindi

The rrolicies aud procedtu'es of t t the results o s tlral rvt pubhcatrou rn a ncl*siou.-
IPI.arlc1irllco-ltttltr.ltsprit.uti:sttbrttissi0ll0rthe.l}lllSlffi nanuscript lir:iliiilil;jlj,:"i::.Hi'Jt;-.liifi:.m,:;:fi:?::-,li::1ll;"Pos"':re,'pa"iar PI:
untitled h1
references

l. A111erican Cancer Societr': Cancet' Statistics. http:ji'w\\llr.cancer.org, 2007 2. Nadji M. Gomez-Femandez C, Garrjei-Azar P, et al: Inuruutoltistocheuristry of estrogen artd progesterore receplors recorrsidetud: experiettce with 5.993 breasl callcers. Anr J Clirr Pathol 133:21-7. 3005 3. ltforales DE. lv{cGowan KA. Grarit DS. et al; Estt'ogell prot}rotes angiogeruc activit.v hr hunan umbilical vein eudothelial cells irr vitro ancl irr a ruru'ine utodel. Circulatiot 91:75563. 1995 4. Shrveiki D. Itin A. Neufelcl G. et al: Patler:rs of expressiou of vascular errck:thelial glowth lactor (VEGf) and \,'EGF recepior$ in rnice suggest a role irt hr:nuonally regtrlated angiogenesis. J Clirr lnvest 9l:??35-43. 1993 5. Takei H, Lee ES. .iordau VC: Iu vitro regnrlation of vascular ettdothelial growth factor by estrogens and antiestrogelrs in estrogen-receptot'positive l:reast cancer. Breast Cancer 9:3942.2042 6. Nakamura J. Savilrov A. Lu Q" et al: Estrogen regulates vascular eudothelial powth'pemreatrilit-v lhctor expressir:u in 7,I?-clirnethylbenz(n)antluaceue-iuduced rat luflllunary hunors. Endocrirrology I -17:5589-96. I996 7. Jail RK. Satabakhs[ N. Sckell A. et al: Endothelial cell death. angiogertesis. and uricn:vascular fiurcliou after castmtiorr irr an audrogen-depertdent ttuttot^: r<lle of vascular endothelial gro*'th thcrr.rr. Proc Narl Acad Sci u s A 95:10820-5. 1998 8. lvtoruiclsen H. Gershanovich Ir{. Sun Y. et al: Phase III shrclv of letrozole ver$us tauroxifetr as first-liue therapy of aclvanced breast caucet in postureuopausal woulen: analysis eif strryival ald upclaie of efficac-v t'om the Lttentatioual Letrozole Breast Cancer Group. J Clin Oucol2l:?l0l-9. 2003 9. Na$roltz .IlvI. Buzclar A. Pr:ltak M. et al: ,{,nastroz{)le is strperior tr: tarttoxiferr as first-line therap-v tbr advancecl breast carrcer in postrneuopausal tvomeu: results of a North Aurericalt glrlticenter raudouized trial. Ariruidex Study Group. i Cliu Oncol l8:3758-67, 2000 10. Borureteme J. Thurlimarm B. Rotrerlson JF. et al: Artastrozole lrersus tatnoxifeu as first-line lherapy tbr advalced lireast caucer in 668 postrneuopartsal wornert: results of the Taruoxit'err or Alinriclex Raudomized Group Eflicacy and Tolerabilit-v snrcly. J Clin Oncol l8:3748-57.2000 I l. Baum lv{. Butlzar Atl. C'uzick J. et al: Anastrozole aloue or in courbirratiorr with tarloxit'eg vefsus tantcxiten alone lor adjuvalt lreahtteul of postttrenopattsal worttett witlt early breast cancer: t.u.st results r:f the ATAC rancloutised trial. Lancet 3,59:? I 3 I -9, 2002 12. Bfiatlagar AS. Hausler A. Schieweck K. et al: Highly selective inhibitiori of estrogeu biosynthesiit y C'CS 2A267. a nelv norr-steroidal aromatase inhibitor. J Steroicl Biochern Nlol Biol 37:1021-7. 1990 13. Bfiahragal AS. Batzl C. Hausler A. et al: The role of estrogen iu the feeclback rcgttlatiort of follicle-stiruulatiug honlone secrretiou irr the ferrrale r^al. J Steroid Biochern Mol Bitll 47:l6l-6, 1993 14. Iveson TJ. Surith IE, Ahem J" et al: Phase I strrcly- of the r:ral nousteroidal aroruatase inlriLritor CGS 20267 in health-v postuenopausal r**onteu. J Clin Endocriuol lv{etab 17:3?43t. 1993 iiffi1,'l,lili1"'*ilf"ffili:f:iilf'.l3,lll;*:?::-.I'il1i.'J"Pos'ir':re'opa";ar 15. Feutara (Letrozole) tablets package iusert. Novartis Plmnuaceuticals Corporaiion, Ea"st Hanover. NJ.2003 16. ('aurpbell SL. Khosravi-Far R. Rossmnn KL, et al: htcreasiug couplexity of Ras sigraling. Oucogeue l7: 139,5--113, 1998 17. Adeyinka A. Nui Y. Cherlet T. et al: Activated uritoqeu-activated protein kirtase expressiou duriug huruau breasl tuurorigertesis and trreast cancer progressiorr. Cllirt C'ancer Res 8:1747-53. 200?  
18. Esteva FJ. Sahin AA. Srnith TL, et al: Prcgrrostic sigrriticance of pltosphorylated P38 nritogen-aciivated protein kinase aud HER-2 expression iu l-r:nph uodelositive breast carcinorrra. Cancer I 00:499-506, 200"1 19. Jolurston SR.Iiead J, Prurcholi S. t't al: hrtegratir:n of signal trarmductiorr irilribitors rvith endocrine tlrerap.v: an approacli to overcorniug iionnone lesistance in trreast caneer. Clin
(larcel Res 9:52.trS-3?S. 3001 20. \Vilhelrn SIr{. C'arter C. Taug L. et al: BAY 43-9006 exhibits broad spectnntt oral antinuuor activitr, aud targets the RAF.1N'{EKr'ERK patltrvav aud teceptor tyrosine kinases irrvolved iu trunor plogressiou ald angiogeuesis. Caucer Res 64:7099-109. 2004
?L Escuclier B. Eiset T. Stadler \\&{. et al: Soratbnitr in advanced clear-cell retal-cell carcinourR. 1{ Engl J lr,{ed 356:12-5-34. 2007 22. Follurrau .l: What is the evicleuce that hrrr.t:rs are angiogelesis dependenfl J Nat[ Cancer hrst 82:4-6. 1990
:3. Weiduer N^ Serrrple.lP, Welch \\.rR. el al; 'I-unror augiogenesis and metastasis--
corelation in iuvasive breast carcittouta. N Errgl J Med -3?4:l-8, l99l 24. Weidner N. Folkmau .I. Pozza F. et al: Truuor angiogenesis: a nerv siprilicant and indepeudent prognostic iudicator il earl,v-stage breast carciuorrra. J Natl Cancer Lxt 84:1875-87. l99l 25. Stnuuberg D. fuchly H. Hilgel LA.. et al: Phase I cliuical and pharnacokinetic study of tlie Novel Raf krnase aud vascular endothelial gorvth iactor receptor ilrhibitor BAY 43-9006 in patierrts rvith advanced retlactory'solid ftunors. J Cllin Oucr:l ?3:965-72, ?005
?6. Awada A. Heudlisz A. Gil T. et al: Phase I satbt.v and phannacokinetics of BAY 439006 adrninrstelecl tbr' 2l da-v-s on/7 days o1g 1, patients rvith advattced. refractorl solid truuorrs. Br J C'aucer' 9?: 185-5-61. 2005 27. Clark.tW. Eder.IP, R,van D. et al: Satbtv and plnrmacokinetics of the clual action Raf kurase and vasctrlar eudothelial gnor.vth tlctor receptor irrhil:itor. BAY 43-9006. in patients rvith advanced. refi'actor-v solid huuors. Cllin Cancer Res l1:5472-80, 2005 28. }{oore Ir,1. Hirte HW. Siu L. et al: Phase I study to tletermiue the safety'and phanuacokinetics of the novel Ralkiuase and VEGF R inhibitor tsA\' 43-9006. aduinislered for 28 clays onr'7 days ofT iu patients with acltanced. refraclor-v solid ftlmors. Arur Oncol l6:1688-94. 2005
?9. Siu LL, Arvada A. Takiuroto C H. et al: Phase I trial of sorateuib and gemcitabine in advanced solid turuors rvrth au expanded cohort iu advuced pancreatic cancel'. C'lin Cancer Res l2:1.1.1-51. 2006 30. Richly H. Heruiirrg BF. Kupsch P. et al: Results of a Phase I trial of sorafenib (BAY '139006) in courbiuation rvith doxonrbicin in patrents with refi'actory solid nanor$. Arut Oucol 17:866-?3.1006 Plrase ['II Trial of Leho.ot. f'] and Sorafenibl as Firsr'Lile T[erapy itt Poshtreuopausal ldrouurr rrith Honuone Receptoi:-Posrtive Locall;- Adr"anced or Metaitatic Breast ('attcer N',7 3 l. Brrkorvski RNI. Eisen T, Szczdik ('. et al: Fhral resulls of the randoutized phase III trial of sorafbrrib in advanced renal cell carcinonu: Srnvirral ancl lriornarker analvsis. J Clin Oncol ?5:240s. 2007 3?. Llovet J" Ricci S. Nlazzaferro V. et al: Soraferib iruproves sruvival in advatrced Hepatocellular Carcinorna {HCC): Results of a Phase IIl randomized placebo-cotrtrolled trial
(SILA.RP trial). Jounral of Cliuical Oncology ?5: X^ 3007 (atrslr LBAI)
33. Bianchi G" al. e: A phase Il multicentered urccxrtr<llled trial of soral'enib (Bay 13-9006)
iu patients rvith ruetastatic breast cancer EC'C'O l3 - the Eruopean Cancer C'out'erence.  
October 31.2005. Pans. France. 2005 34. I{oreuo-Aspitia A. Hillruau DW. Wiesenfeld }vf. et al: BAY 43-9006 as single oral agerrt iu patients rvith ruelastatic breast cancer previously exposecl to anlluacycline andior taxane. Joumal of C'liriical Oncology. ?006 ASCO Anmml N{eeting Proceedings 2a(l8S):,s77. 2006 35. Cristotlnilli N{. Budd GT. Ellis N{J. et al: Circulating trunor cells. disease prog'essiott.  
aud sruvival in metastatic breast cancer. N Eugl J Med 351 :781-91. ?00.1 36. Willett ('G. Boucher Y. di I ouraso E. et al: Direct evidertr:e that the \IEGF-specific antibocl-v bevacizumatr has antivascular effectr in lttunan reclal calcer. Nat N{ed l0:145-7.  
2004 37 Xiong HQ, Herlrst R. Faria SC, et al: A phase I srurogate endpr:irrt stud-v of SU6668 rn patients with solid tlunors. Ln est Ner,v Drugs 32:459-66. 2004 38. Ihonras JP. Arzor:uraniarr RZ. Alberli L). el al: Phase lpltannacokinetic alrd phanuacocl-llarnic shrcly of recourbinant huuran enclostatin in patients witlt advartced solid hunors. J C'liu Oncol 2l:223-31. 1003 39. Geisler .I. Halues B. Allier G. et al: Influeuce of letlozole and anastrozole on total body aromatization and 1:lasura estrogen levels in postmeuopatrsal breast callcet'patieuts evalrtated in a randouized, cri:ss-over shtdy. .I Cliu Oncol 20:751-7. 2002
.10. Bajetta E. Zilernbo N. Noberasco C. et al: The ruinirual effective exentestane dr:rse for endocrine aciivity in advancetl l:reast cancel'. Eur J C'nucer 33:587-91 .1997 41. Lr:ming PE: Exeurestaue: a revier,v of its clinical efficacy aud safety. Breast l0:t98-
?08. 200 I
42. I'herasse P. Arbuck SCi. Eisenhauer EA, et al: Nerv guideliues to evaltmte tlte respouse to treatment il solicl hunors. Eur,rpeau Organization tbr Reseat'ch aud Treatnrent of ('artcer.  
National C'aucer hrstitute of the Llnitecl States. National Cancer instirute of Cauada. .I ltlatl Caucer Inst 9f:205-16. 2000 43. Sminror. DA. Zrveitzig DR. Fr:ulk BW. et al: Global gene expressiorr protiling ol circulatirrg tuuor cells. C'aucer Res 65:'1993-7. 2005 44. C:ristothnilli Ir{. Hayes DF. Budd GT. et al: Circulating tunor cells: a nor.el propntostic tactol tbr lewll'diagnosecl melastatic trreast cancer. J Clin Oncol 23:1420-30. 3005 .15. ir{iles IL{: Perhrsion C'T for the assesslnent of nruroru'vasculadtl': which protocol? Br J
Radiol 76 Strrec Nt-r 1.S.16--ll, 100,1 46. hrvestigator''s Brr:chrne Soral'euib/Raf kinase hrhrbitors. Bayer Plmntmcettticals C'orporation. 2004 47 . Fleiss JL. Levrn B. Clho Paik N{: Statistical rnethods tor rates and propottious.  
Indianapolis. IN. Wiley,. 300-1 il1fi::'il;'ii;ll;*,["i:::ffi :Ji;'.Tf i]m,:;::,:]:?::]H:ff "Pos'1r*e.opaurar  
  
  
nr,I
untitled h1
appentlix a

Performsnce Stutus Criteria  
| ECOG Performance Status Sc:rle   | Krrrnofsky Performance Scale                                                                                                                                                                        |         |                                                                                         |
|----------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------|-----------------------------------------------------------------------------------------|
| Cir"ade                          | Descripliorrx                                                                                                                                                                                       | Percerl | Dercripfiorr                                                                            |
| ()                               | Nonnnl actir.iry. Fully actile. able to cm'r)' orl all pre-diseare perfot'urance rr.ithout restriction.                                                                                             | 1 i)0   | Nonrral. uo corrtplaints. rto ertdeuce of disease                                       |
| 90                               | Able to cafly on ttorutal actiriryl minor *iqns or $ynrl){otlls of cliseate.                                                                                                                        |         |                                                                                         |
| I                                | Synptorus. btrt artrbulatorY. Restricted in phyrically strenuous actirity. brri anrbulalory and able to cariy out uork of a light or sederttat't, rrahu'e (e.g.. liglrt houseuork. office u'ork.,t. | 80      | Nou[nl actilif]' s'ith effbrr: sonre signs or s-volptonui of di;ea se.                  |
| 70                               | Cales tbr self, runble to ctur] otr trorrnal actitit-v or to do active rvork.                                                                                                                       |         |                                                                                         |
| 1                                | In becl "':50oro of the tirne. Arnt:ulatorl autl capable of all self-care. hut urnble to cau-v oil at.v s'ork actilities. Up and abor( rrnrre llun !0% of wakiog hou's.                             | 60      | Retlriires occrl^siottal assistance. but is able to care for rrtosi of hisr'iter ueeds. |
| 50                               | Reqtrires considerable assistance and frequent rrredical care.                                                                                                                                      |         |                                                                                         |
| -1                               | In bed ;,50o,i of llre tirne. Capable of only linrited sell'-care. corfured to bed or chair ulore that 501t of waking hotus.                                                                        | {0      | Dirabled. tequires *pecial care and alsistance^                                         |
| -t0                              | Selerel-v disabled. lrospitalization ilxlicated. Deatlt rrot itrurtittettt                                                                                                                          |         |                                                                                         |
| {                                | I 00o'o Lredriclden. C"onipletel,r                                                                                                                                                                  | 20      | \ier} rick. hospilalization ildicated                                                   |
| disable<I. C'arutot can1. on any relfcale. Totally coutirrecl to lred or chair                                  | Death not irruninent.                                                                                                                                                                               |         |                                                                                         |
| 10                               | tr,loritrrurd. fatal processes pro3ressirtg ranidlv.                                                                                                                                                |         |                                                                                         |
| 5                                | Dead.                                                                                                                                                                                               | (l      | Dead.                                                                                   |
untitled h1
lppentlix b erv york heart

| Class                                                       | dyspnea, palpitatir:n ol anginal pain.                                                                                                                                                                                       |
|-------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| II                                                          | Slig]rt linritation of ph.vsical aclivity: Such patients are cornftrfiable al I'esl. Ordinar-v" physical activit-v results iri tatigue, pa\:itations. d_vspnea. or arrgnal pain.                                             |
| iU                                                          | $'Iarked liuritation of ph1'sical activity: Although patients are courfiortable at rest. tess thau orditary physical activity will lead to $],utptoms.                                                                       |
| IV                                                          | hrabilit-v lo carry ou ph5r5lc6l activit-v without discourtbrt: Syruplonm of cardiac iusufficiency or of angirml sludrome may be present even at rest. \\rith auv phvsical activit\,. increased cliscorntbn is experieucecJ. |
| Soruce: Criteria Couuuittee. Ner,v Yor* Heart Associatir:l. | Inc. Diseases of the heart                                                                                                                                                                                                   |  
Inc. Diseases of the heart  
9'h ed. Bostou. Little.  
Soruce: Criteria Couuuittee. Ner,v Yor* Heart Associatir:l.  
and trlood vessels. Nourenclatru'e aud criteria for diasrrosis.  
Brorvn aucl C'o. t994:2-s3-6.