Phase I/II Trial of Letrozole (Femara) and Sorafenib (Nexavar) in Postmenopausal Women With Hormone-Receptor Positive Locally Advanced or Metastatic Breast Cancer
Phase: PHASE1
Conditions: Metastatic Breast Cancer
Sponsor: Rutgers, The State University of New Jersey

Official Title:
Phase l/llTrial of Letrozole (Femara) and Sorafenib
(Nexavar) in Postmenopausal Women With Hormone-
Receptor 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
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Title:
Principrrl Investigator:
*Role is non-clinical. no 157? r'eqrrired
PltaseliIITrialtlfLett<rzrrl"fanclSorat'et,i,,r
as First-Line Therapl, in Postrueiiofiriusal lfi 'otnen u,ith Hotmone
Receptor-Positi ve Loca ll-v Aclvartcecl r:r lr'letas tat ic Brea st {'nucer
EG
IND#
-f.rtlicare
ll! d,qr*_la-r e sliru! i o n
This document is coufidential anrl the properrl of tlre
\o part of it rrrll]' b. traDsmitted,

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,,.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
l0
l0
l. I .,{ Brci-ock- lNo ntsc;Iltc conng
PARTI('IP,TTtI G INSTITT'TIO
........... I I
........... t 2
[\PERI}'IE:{T,I"L DESIG)i .lJ
P.TTIEIl' SELE( TION CRIT
-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
3.
4.
{
-5
5
5
5
5
5
6.
'7.
TREAT]\,TENT PL.{N.......
?. I GENERAL CONSIDERATIONS
?. 3 TREATMENT ADMNISTRATIoN,.,.,. .., .,.,.,.,
J.4 P}IASE I DOSE \-{oDrICATIoNs oR ESCAI.ATI0NS
?.,< PHASE II TOXICTTY A]\D DOSE M0DIFICATIONS ..
16
l6
t6
l6
16
l'"
l8
t:
22
_-1
?.6 CoNCoMrrAI.i-r \rlfDICATIoNS.........
? SUPpORTI!9'E CARE GUIDELINES,.,.,.,
?.8 .{D}GRENCE C:oN{pI.tA:icE ..............
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
I1.1
I 1.2
I l.l
I 1.4
1 1.5
ll.,l
IMMLI,{OHISTO('HEMISTRY ANALl:sIS
(.m.CULATING'I1;MoR (]Errs
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
2.I .-T RATIoNATE FoR STUDY
t2.
a
,'
_)_

Phase i'II Tlial of Len'orot.f 
rrnd Sorafe,ilrI 
ai Frlsr-Lr,e Therapf iu posrmeuopauial
\\'otttctt rr illt Hortttrrtre Recepior;Poiiiir e Loctrlll .cdr irn.'e.m;:flereirarir BLeasr ( ene el
PI:
t 2.1
35
38
12.2
13.
DAT..I. COLLECTION A\D
TO Bf
ELECTR0MC C.ASE REP0RT FoRM
1.I. 
DATA AND SATETY }IO\I
I5. 
}'I"LTI,INSTITT"I'ION,T.L G
15 I IRB APPRO\:ALS
I.5.: OTI{ER PRL.SIL"*DY I}OCUMENTI
I,1, 3 hTuATIoN SITE \:ISrr,VEETL\I6
1 5.,I IRB CoNTII\'IJEIG APPRovALs...
I 5,5 .A,ME:\$ME}:rS A]\D CoNsENTs..
1 5. 6 PATIENT RECTSTRATIoN
I5.: DATA COLLECTION AND TOX(ITY
I.t.8 DAIA. N.IoNrroruNG AND S0L?C
1,i.9 DAT.c, A}lD CENTER .q,LDITs.,.,.
16.
STATISTIC.{L CON SIDER{
I 6. I PRIMARY AND SE(ONDARY HYPOTHE
I6,? SAMPLE SzE JUSTITICATI0N .,-".,.,.,...,
I 6.] OLIICoME },{EAsLjREs.
l6.d ANALYSTS ...,..............
{9
r3.I
I _1.3
r 3.3
-18
39
-r9
39
39
39
"{.0
,tfl
40
.10
4l
41
,ll
4t
.1t
42
,a{;
42
42
.{l
I -.: POIENTI4I., RISKS,.,.,.,.
I 7. -I CONSENT PROCEDL]RES
18, ECONOMIC/HNAIIICIAL CO}ISTDERATIO}iS 
...............44
19. 
PI]BLIC.T.TION Or RESEARCH flNDnVGS.. 
...^*-....".....44
-1 -
..,^.^..,^ rtO

il,:::.1,'llili1"""*i:5H;:'ti.TII5.t#-I:;;l:?:::li::lfli,posil':re"opa"ia,
PI:
LIST OF ASBRE\TIATIOSS
.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
-4-

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'
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'.
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.
2. Background nnd Signilicance
2.1 Introduction
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.
Plotocol \iersiour a E, l(}1-l
-

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.
2.I.1 Aromatase inhibitors in postmenopausal mefastatic bretst csncer
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
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
-6-

iiffi lilliJii;iff :"i:::m*'lffi,n.,l ;l: tr.I1:',1l,;i" 
po st,,re,'c':pa.,iar
PI:
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
1

PI
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
-8-

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
-9-

*-"'''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.
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.
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-.
- 10 -
Pr otocr:l \:elsion: l, $, :i) 1.1
I

Phase LII Tlial of Letrozot*firnd 
Soralirribf 
a' Fu'rr-Line Therapy irr poshnenopausal
!\'o,,*r, ,r'i,I, Hot 
'e Locrlll' .f.draucEJTi:[tera\raric Breast ('arrcer.
PI:
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-
Pnrtic
Institrrtions
ll

iiil::llllllii"*',["i::"-H$iltlfH,]::,j:?[-,I'i::li.:j"post,ie"r:1ia"ia,
.1. Experimrntnl Design snd *[ethotls
This is an open-label phase UtrI trial to cletemrirre the clinical benefit rate of courbinirrg letrozr:le
and somfenitl it postruettopausal wJmerr rvith prcvior$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$enl r.vitlrrlrawal, rlolt-compliance. etc.).
5" Prfient Selection Criteril
5.1 Inclnsion Criteria
A patient is eligible for rnrollment if all of the follon ing inclusion criteria sre met.
5.l.l Histologically confurned invasive bleast caucer
5.1.? Stage IIIB. IIIC rvith T4 lesion or Stage I\r disease
5. 1.3 ER-positive and'or PR-p,:sitive of prinrary or seconclary hunor tissue
-5.1.4 Wouren are > l8 years
5.1.5 Posnueuopausal stahts det-rned by one r:f the lbllolving criteria:
o Age .s6 or older and history of at least 12 moulhs r.vithout spontaileot$
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
ta
PI:

Phase LII Trial ofLekozo
nncl
as Filst-Lile Therapy irr Postmeuopaural
Locr
I or Jr{etastatic Brealt Cancer
5. l.l I Able to swallorv and rekin oral uredicatiou
5.1.12 Writteu inforruecl consent
5.2 Exclu:rion Criteria
A patient will not be eligible for this study if any of the following exelusior criteris nre
met.
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.
Li
\\,'onsi

Phase HI Trial oi
\\'otrleut.ithHorrrrolIet:.::.,.etffiitaticBfea'tCattcer
5.3 Inclusion of \Vomen and llinoritirs
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.
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.
Palients rvill be recnriletl tlu'ouqh screeni
fbllorved in
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
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.
5.5 Sources or \'Iethods of Recruitment
l4-
rt the

Phase I'II Tlral of Lekozot*f 
irnrl soraferrrhl 
a: F*sr-Lrrre Thelapl.irr posrrrierropauial
\\'trttlerr sillt Hrrrttttrtte Re.'etxotoFFoiii]re Loq.rllv AtlrffiTffiler.rrtaric Brersr ('mier
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
Prr-
sfud"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
\Yeeks
End of
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
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
{see Section I l)
Send to
l5

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,
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:
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.
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.
7.3 Treatment Administr*tion
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.
l6

Phase I.'11 Trial .f Lehozot.Jirutl 
\oraferribl 
a. Frrsr-Lr,e Ther.ap1,i, posrurerropauial
\\'oruen \\ itlr Honlrrurc Rer.eptor:Fo;lrn c Locrllv f dri 
let,r;t:iric Brer.t (.mcer.
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.
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.
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.
7.{ Phase I Dose tr{odilications or Escalntions
7.4.1 Phase I Component
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.
- ll
PI:

. 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.
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.
7.5 Phase II ToxiciQ- nnd Dose il'Iotlilications
7.5.1 Phrse II:
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.
7.5.2 Sornfenib Dose N{otlificafions
Sorafeuib specific rnodit-rcatiorls are outlined in the lbllowing tables:
- l8 -

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
*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.
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
occlur"ellce
krstitute *uppot'live ilteasrues itnmediately and corrtinue sora lbnib
trEatluent
0rade 2: Painfirl
eryrtherna and sr'r,elling
of the hands or feet
altlor dircorufbrt
all-ectilg the pntient's
nonnal activities
l"
occwTence
Inslitute supporttt:e rnefl$rres and consider a decrease ofsoralbrrib by I
dose level.
e If toxicit,'tenrrx fo grade 0*l after do*e redtrction. increase
sorafeuib to full dose (per original dosing *chedule) after 38
days
r 
lftoxicily does ror retrulr to grade 0-1 despite dose reductiorr.
irrterr"ttpt soraferrib freatrneut for a urininrrrur of ? days. rurtil
toxicity has resolr-ed to grade 0-l
r[rhen resunring treatrneul alter do*e iutenrrpliorr. t"e$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
- 
clf -l
occtuTe[ce
As lbr first occllflelce. txrt upou reriutrilg sorafenitr trentrnent. decrease
dose fo the uext lower dose level irdelinitelv
"rh
-l
occtuTence
Decisiol rrhether to discontiuue soratenib lrefftulent slrould be rnade
based on clirrical jrrdgeuteui and patieut pretbrence
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'
occl^uleilc€
Llrtitule srqrportite lneasrreri flld ir[€l"t'upt sorafenit: treaturenl for a
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
2.,1
occtul.ellce
As for t-rst occrul'euce. but upon resuuring soral-euib tteatrrrnt. decrea-se
tlose to tlre lrexl lorver dose lerel incletinitelv
rtd
-:l
oc{.tuTerrce
Decisiou rvhetlrer fo clisconfiuue soraferrib treatuleul should be rnade
base<l orr clinicnl judaenrent aud patient prefereuce
I9
Plotocol \:ersion: 7iE,'20 14

as Firrit-Lile Therapy iu Postrnetropaural
etastatic Breast Carcer
Trble 7.5.2.? Dose llodilicltion for Sorlfenib Associtted Non- HemttologicToxicitv
Toxicifi'
Gracle I
Grade 2
Gruele 3
Grade {
l{on-
hematologic
C orrtinue at the
same dose level.
Coutiuue al tlte
same do.se level.
Withhold dose turtil
toxicity is grade s l.
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.
If toxicit-v does uot
resolve rvithiu 2
lveeks patient rvill
discontinue treatment"
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 a second tr:xicity
occurs the patient r.vill
cliscoutiuue treatrnent.
- iu -
PI:
Plotocol \iersiott: 1,8:'30 i J
T

l*:1,111;tii;i,1::i::,lHr:l;Hi::il.;;t}::;t:?l::lflil:,:"P'si':,e':r'pa.,iar
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'
Drry I of An-v C.vcle
.\)r{(' ..:: 126QipL aud or
platelets ",: 100.000,'trl
Hold Treatruent
* CBCs shoulclbe
repeatecl rveekly until
recovely
If corurt recol.ers rvithiu I
rveek
Resuure treatrnerrt at full
clo.se
If count l'ecovers withirr 2
rveeks
Reduce I dose level for all
srrbsequeul c1'cles
If corut cloes not recovel'
rvitlrin 2 weeks
Discoutinue prr:tocol
tleaflneilt
An-vtime during
treatment
Febrile episocle (-.' 38.5"C)
accoruparied b-v ANC couut
",; l200ipl
Ret{uce I dose lel el tor all
subsequeut cycles.
A subsequent febrile
neutropenic er.'eut
Discorrtinuntion of protocol
therapy
"I oxicitl'
Gnrtle 1
Grarle ?
Grade 3
Grntle {
Hematologic
toxicifies not
Iisted lbor-e
Corrtinue at the
saure close level.
C'ontiuue at the
saure dose level.
Withhold close rurtil
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.
:l -

iifi::"Xlitil" ".""i:::H ::ilffi f :ilm,:,:lx: ?rlt:liJ;i" 
Po s'fr':re,opa'lriar
O',7
Trble 7.5.2..1 Mnnlgement of Treltment Emergent Hrpertension
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.
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.
Grade
}I*nagementlNext Dose
Grade I
('r"rusicler increasecl l]P monilol ing
Grade 2 aspuptontatic and
cliastolic BP.r I l0 rruu Hs
Begin anti-ltlperteusir.e therapy and cotttirttte agent.
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 arrti-
liyperteusives 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.

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.
:i-

Puase I,II rrial of Letrozot* ,f 
.rn't so'nf'*bIl,I:ifi:!iL-rl'il1i.'.J" Postureuolattsal
\\:orttett uitlt Hottttone Receptor-Posltl\ e Locilly
-
Acl'erse e\iellts rvill be recorded otr eleclrorlic case" repol'l t'orrus itt accr:rdatlce with I study-
specitic data capflue Plal.
8.1 Definitions antl Reporting Requirenrents of Atlverse Events/Reactions
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.
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
Protocol \,'ersiott: ?i 8''2014

il,}:::K'Iiii1:j,T,x"i:f-mff:riif$H,}:,}:?[^}[:1r:;,'Postrtrerropatrsal
N',E
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.
8.1.5. Definition of Arlverse Drug Reaction (ADR)
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.
headache. nausea, votriliug. diarr{rea,
sprained anlile) rvhicli uray ilterfere or
not constitute a sutrstatrtial clisnrption.
Is a congenittl urcnuth'or ltirth de,{ect.
8.1.6. Definition of Serious Adverse Drug
A Serious Adverse Drug Reaction is att
seriousness as prer.iottsll, delined ancl has
dmg.
iutluenza. and accitleutal trauma (e.g.
prevent everlda.v lit'e frrrrctions bttt dcr
Renction (SADR)
event that meet.s any of the criteria tbr
a possible catxal relationship to the sttrcly
reporteri to I
ruusl inclucle the
rvlro experiencecl the adverse event exists
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
:5

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.
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
T[e O]{RS rvill be respousible lirr lortarcling SAE reporls tot he strtdy sttpporler
-:6-
Plotocolt3i|

ii]il:*1ili1;i,1",["ilf.H::i.:Jiii:'i].m,:I^|l;]:?'Ji.I',fl1l];"Pos'lr':re'o,a'lriar
n,,I
II
L
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
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'
aclverse evellts
the last dose of
r

ii,fi :"lili ;1"''"*i:l:H;:t;'.xftlffin|;;:t;l[:ll1J"Posu';re':ro,a"rar
-
8.1.11 Reporting Serious .tdverse Evrnts to the Food nntl Drug Administration
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.
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).
9. Treatnrent Ev:rlu*tionlClriteria 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)'-
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).
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
:S

ii]:::""ff l'i1;lH,["i:rm::fffi f i:.H|,n*,1: ffiIt:lpv 
i, Po s'lrne,opa'luiar
Pr,I
elh15ious. lynpharrgit'. .,r115,ipuhuouis. iuflanuuatotv breast clisease. abdourinal ulasses
(1ot ficrllorved by CT or IvIRI). and cystic lesious are all rron-rneasru'atrle.
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$e. There ruay be
occasious whel progtessive tlisease is su-spected brtt catutr:t be firlly characterized. Iir these
cases tfie trenting pliysician may decide to continue treatrueut for orre or two cycles betbre
reassessulert. it'-6e1she tbels it is il the patiert's trest interest and the patie0t agees to
contitttre treatmerlt.
9..{ Non-T*rget Lesions
All other lesious (or sites of tlisease) rvill be ideutifieei as non-target lesious arrcl rvill lre
recorclecl at baseline. Non{arget lesions incltrcle measruable lesions that exceed the
uraxiulutr luntrers per orgarl or total of all involved organs as r'vell a$ 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.
:9-

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$ary artd detenuirred b-v the
iuvestigat6r. 
-l 
-A"io*"al confir:nation of the neoplastic origin of any efhrsion that
appeals or w.olsells chu^irrg treaturent rvhen the ureosrtrable tumor ltas ruet criteria for
respouse or stable disease is uraudatory tr:r differentiate betrveen respoilse or statrle
dislase (a1 effirsiol rnav t:e a siile ettct of the treatltent) alcl progressive clisease'
9.6 Response Criteria
ofT
9.6.1 Evrrluation
slons
C'omplete ResPonse (CBtr
Disaupearattce of all target leqgg
Parlial Resporrse { PR):
At t-.tt " 30'n .t.crease in tlte sttut of the longest
clia[reter (LD) of target lesious. taking as retereilce the
Proqressive Disease iPD) :
f ilre tn of target
lesions. taking as refereuce tlte sutnllest sttttt LD
recordecl sirrcl the lreattnenl started or the appenrance of
one 0r rr]ore lle\Y lesiotts.
Stable Disease (SDJ:
N.itt**.*acieut sluinkage to quali$' 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
Le
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
ruairrtenalce of hunor malker level above the nonual
lirnits.
hrcotnplele ResPottst'i
Stable Disease (SD):
Apl**r*e;tot " ot lllole new lesions ancl'or
,ri.ot,i.'ocal pros1'essiort of existing no*-ta'get lesions'
Progressive Disease (PDJ :
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
-10
Protocol Versiotr: l8jlg-U

i-m|Xlili1;ifflJilf-H::'i;'."iilf1l.m,:X,*:'J::.I'i:1i.li"Postrne'lropa";ar
-
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
C'R
C'R
PR
SD
PD
CR
hrcoruplete
responselSD
Non-PD
Non-PD
No
No
No
No
CR
PR
PR
SD
PD
PD
PD
.tuiy
Pt)
Yes or No
Yes or No
Yes
tur)'
An1'
Atty
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'
9.7 Confirmltory Measurement/Duration of Respon;e
9.7.1 Clonfirmation
To be assigpred a stahts r:rf PR
confinued b,v repeat assessmeuts
the ctiteria tbr^resporne are lirsl
at 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
Pr otocc,l \:ersiott: l'E :l)1-1
T
- 31 -

i],T::"1JlIi]i1;l*,l,x#f:jirll}m}:fi:?::.,l,fi1iiIJ,,Postlllertopartial
PI
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"
1 1. Laboratory Evalultions and Procedureslcorrelntive stutlies
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'tin-
erlbeclcle<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
Protocol Versiott: ?; Er?0 l4

.*:*lJi-ft,i1;lff f i".:'m.,i.:-:;if *m,:*;X;?f.Ifl1iJ;"Pos"'lre'opa'l*ar
nr,I
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'
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
l-i -
Prof ocol Vemiou: l-, S,'19 !1

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 stanclald-
ot'-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.
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
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.
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).
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
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.1-
meth-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.
-35-

i,l:::.lllliiil"rL-r'"i:r.:HirJi::fi f ilIF.",n:fi:?i:.I'i::1$"Post,re,opaurar
O',7
Storage requirementsl Stabilitl.: Tablets are slable al roortt temper:attue. Do not
store above 35*C (7?*F). Store irr the original package.. Tlte curent shelf life
is 36 ruonths.
Route of aclministration: The dose of soralbnib to be taketr by patients rvill [:e
cleter:linecl t)'our the phase I conrponertt of the trial. Soraferlib is available irr
ilulecliate-r'elease preparations and thrm the active irrgledient is cortrpletely dissolved
in a shorl penorl of tinie atter oral adttriuistratir:u of fihn-coatecl tablets. Sorafenib
should be taken on an eurpty stonrach" at least I hour befr:re r:rr 2 hr:urs after a ueal.
Tablets should be srvallorved rvhole, uot cnrshed ot'cherved. 'uvith 8 olulces or 150 ml
oi rva{er. Il shoulcl not tre ta}ien rvith grapeiiuit juice.a6
Expected toxicities: Ach'erse Drug Renctions in patientr in multiple clinicrl trills
I'IedDR{ cotled
System Org:rn Class
Verl'Cornmon
> 100/0
Conrmon
> 19,6 to < l0Yo
I-rncomnton
> 0.1Yo to < lo/a
Irt'ectiorn aud
infestations
Folliculitis urt'ectiort
Blood artd lltupltaric
syslenl disorders
L.r.nrphopeuta
Leucopenia
Neutroperda
Aneuria
TluourbocEoperua
lnuntue syslem
disorders
Hlpersensitivity
reactiotts iincluding skrtt
reactions aud tuticaria)
Erdocrfute disorders
Hr,uothyroitlisnt
Nletal:olisur aud
mrtrition clisortlers
H-rpopltosplmtelda
Anorexia
Hlponatrertua
Dehr,clratiou
Psychiauic clisorders
Detrressiori
Neryous sysleln
disorders
Peripheral sensory/
neruopatltv
Reversible posterior
leukoeucephalopathv*
Ear zud laby'irttlt
disnrclers
Tiurirus
C'ardiac disortlers
N.{yr-'rarclia I ischettda
and irfalctiout
Congestive ltezu't
failure*
\,'ascular clisolders
Hernonlmge (including
gastrointestinal* and
resptratory, tract* atttl
cerebral heurorrlmge *)
H\.?erlettsir-rtt
HJpetensive ctisis*
Respilatory. thoracic
ancl urediastiual
disortlers
Hoarseitess
Rltiuonltea
Gastroiutrstinal
disr:rders
Diarrhea
Nausea
Coustipatiott
slo ttts_Iir (i$Iditg. sE
Gaslro esoplmgea
reflux disease
-16-
Plolocol \ier:iotr: 7, 6,'lQ1,1
I

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
> l0o/o
Common
> lo/o to < l0o/o
flncommon
> A.Lo/o to < l7o
Vondting
rurouth aud
glossodlteal
Dyspepsia
Dysuhaeia
Palcreatitis
Gastritis
Ciastrointestinal
perforaliorr*
Hepato-biliary
disorders
hrcrease iu bilfurrbin artl
iatutdice
Skh and subcutaneous
rissue disorders
Rash
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
aurl breast disorclers
Erectile clyrtiurction
Grnaeconraslia
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
Increased lqrase
lVeiglu decreasecl
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
Protocol \elsiou r,E, l()1,1
-

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.
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'.
13. Dltl Collection and Records to be Kept
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).
_-1S_

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 l-
-ia 
its 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.
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^
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$'ess
reporls rvill lre plovided to participating irrstinrtious tor^suburission to local IRBs.
1"{. Drts and Safeh }Ionitoring
N{onitoring of this shrd,v r.vill occru iu accoldance rvith the
NC'I approved Data aud Salbt.v Monitoring Plan (DSMP). .fur "initiation audit" wi
conclucted try' OI{RS Qualitt' Assruance statf in accordar}ce rvith the DSI\,{P tbllorvilg
em'ollureut of the firsf tu,t-r (]) or tluee (-1) patients. Sutrsequeut auclits will occur on an aruttml
basis if the finclings trom the initiation nudit rvere satisthctor!'. lr{ore ti'equent audits of Jratient
clata ant'l stu<ly coirduct rvill occrr if uece$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
15. Multi-Institutionnl Guidelines
15.1 IRB Approvals
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
-19-
Plotocol \:ersiou: i, 5, 2ll i:1
I

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.
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
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.
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
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
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.
15.7 Data (lollecfion and Toxicitv Reporting
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.
J0-
I 
I
\\'uurerr uith Horrrrorre ne.-ept.riPolirir e LocrII1' Arh1TrEffi[j
PI:
cousisteucy ivitlr the
appror,al prior to

iil:li,i;L lilii;ifflJfl fG::,il:ifi Ii:.H,:;:*: ?}",I'AlIH" 
Po sh':re,',a"ia r
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'.
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
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'
irr
in
-Jl
Plotocol \.'ersiort: 1; 8, 3l^) I"tr
I

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'
16.3 Outcome }le*sures
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.
16.-l Analysis
Tirne to progression antl overall srur,ival rvill be suuunalized using the standard Kaplan-
lvteier 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.
17. Human Subjects
17.1 Subject Popul*tion
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.
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
- +-
Plotocol \ietiiott: ', E :()ll
I

ii$:"illlilil"*-,["i:r":.H[il:iiifiil#r:;:fi:?:'.'.]fl11'.i"Post're"opa"rar
N',7
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.
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).
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.
- {_t -
Prr,rtocol Velsiott: ',S 3()l.l
T

il,fi:1Xf;'ii;iff ["i:[ffi :t;'.Hf l].iltil]:fi:*..I'[:1,t;"Pos'1r':re,.'a"sar
nt,E
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.
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.
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.
19. Publication of Resenrch Iindi
The rrolicies aud procedtu'es of
t
t the results o
s tlral rvt
pubhcatrou rn a
nanuscript
ncl*siou.-
IPI.arlc1irllco-ltttltr.ltsprit.uti:sttbrttissi0ll0rthe.l}lllSlffi
-d4-

lir:iliiilil;jlj,:"i::.Hi'Jt;-.liifi:.m,:;:fi:?::-,li::1ll;"Pos"':re,'pa"iar
PI:
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Protocol \:ersiott: ' E':Ll l{
T

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. 
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(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
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taxane. Joumal of C'liriical Oncology. ?006 ASCO Anmml N{eeting Proceedings
2a(l8S):,s77. 2006
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37 
Xiong HQ, Herlrst R. Faria SC, et al: A phase I srurogate endpr:irrt stud-v of SU6668 rn
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38. Ihonras JP. Arzor:uraniarr RZ. Alberli L). el al: Phase lpltannacokinetic alrd
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39. Geisler .I. Halues B. Allier G. et al: Influeuce of letlozole and anastrozole on total body
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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.
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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
Protocol \:ersiotr: ?, 8rl0 1',1
-4i -

il1fi::'il;'ii;ll;*,["i:::ffi :Ji;'.Tf i]m,:;::,:]:?::]H:ff "Pos'1r*e.opaurar
nr,I
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
disable<I. C'arutot can1. on any relf-
cale. Totally coutirrecl to lred or chair
20
\ier} rick. hospilalization ildicated
Death not irruninent.
10
tr,loritrrurd. fatal processes pro3ressirtg
ranidlv.
5
Dead.
(l
Dead.
:18
Plcltocol Velsiou: :; E,-:0 1"1
I

a;s Filst-Lile Thelapy in Posturuopaural
.elastatic Breart C'ancer'
,,lppentlix B
\erv York Heart Associ:rtion Criteria
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.
Inc. Diseases of the heart
9'h ed. Bostou. Little.
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.
-rtg-
Plotoccrl \,'ersior: 7,'8, :0ll
r