A Phase 2 Trial of Liposomal Doxorubicin and Carboplatin in Patients With ER, PR, HER2 Negative Breast Cancer (TNBC)
Phase: PHASE2
Conditions: Estrogen Receptor-negative Breast Cancer, HER2-negative Breast Cancer, Progesterone Receptor-negative Breast Cancer, Stage IIA Breast Cancer, Stage IIB Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Triple-negative Breast Cancer
Sponsor: Rutgers, The State University of New Jersey

 
 
Official Title: 
 
 A Phase 2 Trial of Liposomal Doxorubicin and 
Carboplatin in Patients with ER, PR, HER2 Negative 
Breast Cancer (TNBC)  
NCT number: 
 
 02315196  
Document Type:  
 
 Study Protocol  
Date of the 
Document: 
 
 10.18.2021  
 
 
 

Title: A phare I Trial of Liposomd Doxorubicin snd Corbopl*tin in Fntients with ER, P& HER2
Negative Breast Cancer (TNBC)
Suunolted bv:
I
Carboplatin
Psclitaxel
Compnry
Orlho Biotech
Various manufactuers
Various nmnufacnu'ers
II!:D #
NA
NA
NA
DrugSupply
No
No
No
Thfu documtnt ls
*qrydr&os,
tfffi lktMf hr *.
fi&klt::ffilx&
Protocol Version: l0i l8/30?1
I

l.
2.
patierts with ER- pR- HER2 negiltive breast cancer (TNBC)
TABLE OT CONTENTS
ruRrosBlsPf,,crFrc ()BJECTTYES "'""""""""' 
'""'"""""""""""'6
B^ICI{GROIJND A}$D SIGNIrICA}TCE 
...........,...,.8
2.2OrrcoMEsfonfrupr^e-llrcATrvEEREAsTCA!{cER""" 
"""""""""'8
2.3 CHEM0TIIE*rY ron Tnr rnr^TMm{T 0r EA&LY STAGE BREAST CANCER""" 
'-""""""""" """8
3'4 RATI.NATE F'RC.lrBn.{AToRIAL TI{ERA,PY wmr e-.rHn,qCYCLINEs AND CA*B.PI.ATIN.,.....'...'-.,.,.'...,.,.,.,1:
2.5 NEX'TGENEB.A.TIONSEQUENCING()TT,*o**r*o*p^"'*:iwrn{TNBC """" """""""""'14
PARTICIPATING INSTITUTIOIfS...... 
.................17
EXPIRTMtr!{TAL DESTGN A:t{I} METHOT}S""""""' 
"""""""17
PATIEI{T $ELf,CTTOI{ CRrTE&IA" 
""""""""""17
5.3 INCLuSI0N0TWoMENANDIVIIN0RITIES'^' 
"""""" ""19
-.-....,...19
11
6.2 PAr}IOLOCY AND CORX'ELATTYE SjrUDIES,.'
6.3 MUTATTONAL AT.IALYSI$GBIO}fiC TIROFIUNG, ",
,1
.?4
.?,4
.24
.24
5.,1 cs}nErArrvE STt DIES-.......
3.
4.
{
6.
6. 5 PATIENT.DERIVED )(ENOCRAFTS
7.
,'Q
?.2 DosE CAr"cuI"aIIoN
?.3 TA,SA IMENT ADMINISTRATION
?.4 DOSE MODIFICATIONS
?. 5 CONCOUITAXT MMICA'TTONS
?.6 SUPPORfiIE CARE GTJIDELINE$. " ",
?.? AD'IRSICdCOI#I.IA}'TCE
S"TOXICITYMONTTCIRI:\G.A'T\"DAI}}:ERSEEVE!{TRETORTII{G
8, I ADVER.SE EI.ENT REFORfiNG REQUREMENT5
8.? DErs{moN or SERIous AD!'ERSE E!''lENTs (SAES) '
8.3 DEF$lm0?.r or RrL"erED
8.4 DEFI}ITrION OT UND(pECTED
28
30
37
38
-J/
,38
l9
40
9. 
TREJITME}fT EVALUIITICII(/CRITERIA
40
-1-

10.
ll.
12,
doxonrhicin and cn*oplatin in ptients with ER. Prt HERz negath'e breast cancer (TNBC)
ssMovALorPATIEIYT$FR(}MsTtiDYlorrSTLIDYCRITtrRIA.........................45
LABORATORY EYALL'AfiO!$S,-.'""""' 
"""""""""""""'45
PHARMACEUTICALI!'$OAIIATION """"""" 
"""""""""'46
12.4EFIRIIBICEII{YDX0CHL0NDE(ELLENCGET)""""""49
13. 
DAIA COLLECTION AND RECORDS TO BE I(EPT 
"""'50
I}.3 DATA SUBMISSION T$dEI-ETS ANDFORMS..' 
"""""",50
"" "'""' "5I
13"4 REpoRTs
l{. 
D.{.TA.A.II{D SAFETY M0Ii{rToRrNt}"""""""" 
""'""""""""51
t5. 
ST.A.TrSTrC.{L C0NSTDEAATTON$""""" 
"""'52
16. 
ETHTC.{.L AND REGTTLATORY CONSIDER4'TIONS""""' 
""""""""""54
16.S INsmmoNAL RE\r'IEw BoARD AFPRoVAL""""""""" 
""" """""54
......56
17. 
IIL&IAT{ SUBJECTS
18. 
ECOI{OMIC/FINAI{CIA,L CONSTDERATTONS""""*" 
""'*---"""""""'57
19. 
PUBLIC.A,TION 0r RESE"A'RCrr TIIIDINGS" 
"""""""""""57
....58
APTENDH.A,.PERFORMANCE ST.ATUS CRITERIA 
".."""""""""'59
.A}PENDIXB-NEwY0RKrmA}rrAssoCIATIoNCIIITERIA,...............".-".......70
ApPf,NDU(C -FACT'g QUAT,ITYOF LIpE SURYEY"* 
"""""'""""7r
ArrE!{Dfir}*PrrrsBUR(}II SL&Er QuATJTYT!{r}8X""""" 
""""'"""""?4
A.PPENDIX E - CLINIC.AL nISTNESS ASSESSMENT 
""""""""78
A?PENDIXT *IIf,RTAIIOTE INDEX.""". 
.......,...?9
-3-

LIST OF ABBREVIATIOI{S
AC
AC-+T
AE
ANC
ASCO
AUC
BRS
BUN
CAR
CBC
CIyIF
CT
CT CAP
CR
CRF
CTCAE
CTX
DFS
DOX
D$MP
ECG
ECOG
ER
FAC
FDA
FGF
GRD
G-CSF
H}I
I{R
IHC
IRB
ks
mL
NCI
NGS
NIH
NSM
OHRS
OHRP
os
P
PPE
Adriarnycin (doxonrbicin) plus cyc\$ospharuide
;e; 4;y.les followed by docetaxel x 4 cycles
Adverse Event
Absolute neutrcPhil cotutt
American Society of Cliuical Qncology
Area under *re curve
Biospeeime*r S'epository Servic e
Btoodtuea uikogen
Carbopl*titt
Cornplete blood cowrt
iyJipft"qpn-*ide. methotrexate, and fluororuacil
Computer TonroPaPbY
Computer Tomopaphy chest. abdornff1 pclvis
Compl*te ResPan*e
Case Repcrt Fonn
Comnrou Termiuology Criteria for Adverse Eveuts
CyclophosPhamide
Disease Free Srtrvival
Liposcmal doxonrbicin
Data SafetY Manitoritg Plan
Elecrocardiograrn
Eastern Cooperative Oneolog5r Gronp
Estrogen RecePtor
Fluoiruacil, doxorubicin, and cyclaphnsphami de
Food snd Dnrg Adnrtnistrctiou
Fibroblast Grswth Factor
Gross Residual Disense
Gramrlocyt* Colony Sfimulating Foctor
Depcrtrnint of Henlth and llrmrm $ervices
HomonerccePtor
Im,*xrohisto6[grn i s&y
Instihrtionnl Review Board
kilograms
urilliliters
National Caucer Instit$te
Next Geaeratioa Sequenciug
National Institutes sf Health
Nousense mutatiou
OIfice of Htuuas Research Seruices
Of{ige of Human Research Protection
0versll survival
Faclitaxel
Palssr-Ftentar Erythodyse'$thesia $ya&ome
-4-

PBI\{C
PCR
PD
PDX
PFS
PHI
PI
PI3K
PR
PgR
PSQI
RFS
RTK
RWJLI}I
SAE
SD
sCr
SGOT
SGPT
TAC
TNBC
ULN
WP
Peripheral blood mononuslear eells
Pathologic conrPleta re$Pfirse
Progresrive Disease
Patient DedvedXeuoPrft
Proggession Fres Survival
Protected Health Infonnation
Pdncipal lnvestigator
Phospli*tidylinositol 3-kirrase
Partial ResPonse
Progesterone RecePtor
Pittslilrgh SlrcP QrmlitY ludex
Recurreuse fr*e *rwival
Receptor tYrosine kinase
Rob& \l/ood Johnson Uuiversity Hospit*l
Serious Adverse Event
St*bls Disease
Senrm creatinine
Senrm gluhmic oxaloacetic bansaminase
Serum gtutamic pynwic tnnsnmiu*se
Docetaiel, doxonrbicin, and cyclophcsphanride
Triple negative brea$t cfftcer
Upper limit of normal
Weekly paclitaxel
-5-

1. PurPo*t/SPeciIiu Obimfives
i.|-'ffi:r$?::i#t"rrtris st*dy is to derennine the rate of parhologic courpllte respons* *lthtreaturent of
liposorual doxorubicin *J "*u"**tl" i" p*ii*Js with ER, IIi, HERi"negative breast eancer (TNBC)' Patients
will be enrolled to receive the following d.ut*urrt, foru cycles of neoadjulaut carboplatiu and.liposomal
doxnnrbicin administered every ?g days (*;tp}-* eui :, liposomafdoxorubicin 30nrg-lml) then undergo
definitive breast sur*ery {bllowed by 12 weeks of adjuvant paclitaxel B0 rug/rn, admini*tered weekly'
1"2 $scondrry Objcctives snd Eudpoints
l.?.t To detennine the resrraence free $tur,.ival (RI's), ?-year RFS, and ov*rall survival (os) after treahnent
with neoadjuvaut lipoxour* aoron tricin and caibopiatin followed by defiuitive bre*st surgery ard then
weekly pr*fm**f io patie*ts witb ER, Pg8? }IER2 negntive lreast oarmsr'
Endpoinl:RFS, defified as time to local recurreuce followiug sur-$e{, regional rec$rrence, distant
recurrene8, or death fronr any causr prior to recurence or secondprimary esncer followittg
initiatiou of chemotherapeutic treatment. os is defiued as tinre frorn initiation of chemotherapy
until death from anY couse'
l-?.2 To describe the mutational spectrum of fumors formd in prirunry, uotreated ER' P!fi'' HER2 uegntive
breast ca&cer and tlrcir associatior witb pathologic colnplete response to neoad.luvant doxil aad
carb*plntin.
Endpoint:Tumor sanrples wilt be submitted for correlative science studies to evaluate predictors
of stndy therapy benefit. hnmrrnohistochemisby 6{"lor FISH studies will used to confinn
amplifications or trapslocations antl detennio" ilr. association betrveen genomic alterations and
altered p*r"io expression and downsheau: effectors irdicatilrg activatiail of that pathway'
1.2.3 To determine &urctional siguific**ce of genomic landscape in predictitg dnrg response using patieut
derivedxenogaft (PDX) and er vrvo models'
Endpoint: pDX and ex vivo n$says will evaluate for sensitivity to paclitaxel ar
.y*r"prr"*prr-*ic", t*rg"t*a -s"ril ;;i;tt;*.d on genomic pofile- standard cytotoxins' or the
courbination of targeted agents with standard cytotoxi[s.
1.3 Tre.stment Schemr
-6-
ritte : A Pt,c. :-gle!3lllggi,Eg{
urd c*rboplatin in p*tients with EF* PF* !IER! negntive breast cancer ffi-IBC)

ffiffifionrbicirrarrdcarboplatilrirrpatierrtsrr,ithER.pR.HER?rregativebreastca!}cer(TNBC)
Biopsy-proven ER{FgR-/H ERI-
breast sancer
,t
lioosomal doxorubicin 30mg/
' m2 + carboplatin AUC 5,
q4weeksX 4 cycleg
.t
Defi n itive breast surgery
pathologic
Complete ResPonse
inrinrary outcome:
" rate of PCR)
l..l PrimaryHyPothesis
Tle combin*tion of carboplatia and liposomal doxorubiciu delivered neoadjuvantly will demonstrate clinical
activity for the treaffieut of pctieuts with triple legative breast catrcer'
1.5 $eeondarYllYPotheses
l,r.l The combinatiou of carboplatin and liposonral doxorubicin delivered neoadjuvantly followed-by
deliririve **t"ry *a p**nt**l will have measurable benelit iu reeurre0ce &ee survival and overall
survival wUeiused foittre heahuent of patients witb triple negnfive brea*t csucef'
r.5.2 The mtrtatioual spectrum of priurary, usheated ER' PsR' HERz negative breast carcer will demonstrate
associations with pathologic coluplete response to ueoadjuvant doxil and carboplatin'
l.s.j patient derived xenoggaft and ar vivo nrodels will be usefrrl far ruodeling triple tegative breast cancer and
for determiuiJg [;;ii*rti;ipprificance of genomic landscape iu predicring drug respoose'
,
2.1
ffiffi-xff:ffiffi; com$ror rype of noncurruleous caocer among wome,-i[ &e united states' with
, 
t' 
4nt, 
ftl 
af,^-^^rror 
lrrooet^rrlrr,rl'
ffi1fiffiil1fi,friffi;;;;J.f ilsive brcast caucer expected irr rot: [1]. Moreover' breast caDcer
--,lrl. 1o (1o avtcntorl rl*stlrs fforn
lfl::ffiX$|] ,,* ;X;f""..r-r "r 
caucer deaths i* women. with Eir'ozo expected deaths from
L-^ l^^*^--o,{ 
ttr ') ?Qz. nPf
ffi;ffiHffi ;i,r. ;;* ffi, il"*,"rLa**ti, yr: fo, b'".'l :1::w
l;*xtrffi # jl:i'l*;l:::;mx'#,i-,1'l'i,1:*i,LTlruffi
I.t+
I
I
I
I-ll
ll{c
Nextgeneration
geguenclnB
IHC- for tumors
with rapld
response bY
cycle 2
Gross reslduel disease
Backgrountl antl Signilicance
Brea s t C an cer S&tislics.
.t-t
lHc
Next-generation
seguenflnS
'{* o*"""r'
| 
'pitlitbrsl
| 
.c1*l*Ph*rPhr*riide
| 
"TarHata* aEeniE
I trzs*d o* t{S5
I
I
I
I
t*.-*u,,r, ,,* ,*r, ,r, 
n" ' u ' t-'t'-t 
u u' t'n'tl !
t:
paclitaxel
80 mg/m2 weeklY x 12 doses
-7-

stages of breast esocer, aud the efficacy of treahuents for earry stage breast carcel has improved
substanriatly. For instance, the S-year sunrival rate for woulen y,_tg1l].r*::*3:*::jt*ytrt;1xi:j
iXffi::Xt?l,x iffij,,T" ;ffi"il ss"6e,i, today [l]. unfo*uuarely, approximatetv 20e6 to 250/o of
p"il"*i rt1l develop reeurrencs and ultiurately succurnb to tlreir disease'
2.2 Oxlcarxes For Triple Negative Breast Cancet
Although rece,t ui"***Jio detsction snd treat&eut lmve resulted in ixrproved outcomes br pntients with
breast cffrcer overell, lvoilrer with the fiple negative hreast csrcer (TNBC) subtype rgltinue to bear a
disproporlionate burden of mor.bidity aud *"rt tq associated rvith this disea*e. TNBC, i'e' estrogen
receptor (ERi uegative, progesterone receptor (PgR) negative, HERS negative lrreast cancef' represents
10g6-20% of invasive br"east ..rr..r* *itl, , proi*ntiiy to affect yoturger women [2]' Moreover' stage I-[I
TNBC suutype: qil is associated with arr r-fud greater risk of breast cancer death than receptor-positive
h.*ors. ti1 fra* bigher risk af death particutarly.i" tfrg first rro years a\r diagnosis' *nd (iii) excess death
ix relared t" hih";;[oi*rt*t aii**se sfikctinglvitcl o'gans such as the h*rg and brain [?]'
2.3 chemotheropy For The Treattnent af Ecrty stage Breast ccncer.
The value of cheurotlrerspy, uotrr aajurant'**a i*oua.1uvaot, in substautially redrrcing the nsk of breast
cancer rec*rence aud death in early stage breast ca$cer has been consistently demonstrated froru the data
of iadividual radornized trials *d umir**d in the Ear$ Breast cancer.Trialists' collaborative Group's
(EBCTCG) l5-year meta-analy*ur.o*l*iug dala from the individuat chemot[erapy ilials [3]' Therc are
*rany cbemothernpy regimeus with;*teblislrei effic*cy and sa&ty data" However, the EBCTCG has shorvn
tbat a'tluacycline-coptaiuing m-*p*-, r.t" sequentiai doxonruicirr and cyclophosphamide (Ac) followed
by taxanes, redlrce the risk of recurrenlce by rlPr'o and the risk of death by 16% eompared with
cyclophosphamide, metlotrexate, and fluorouracil (CMF) combinations [4]. As sueh' regirnens utiliziug
a'tlrracycli,e is combilation with "y"roprrorphaniide 
have becorue the staudard of care in the treatment of
breast cancer"
2.3.1 Ant hra cyc line'Based Regimens l*corparuli*g -Taxanes'
The role orto*"* "s pai of adjuvantilrei'apy for treatrnent of patieuts with breast caoce( was estabtrished
with the clinical shrdies CALGB 93aa and I{darp B-?8 [5;6]. Bottr the CILGB and NSABP B-28 studies
demonstated red*ced risk recurren.* *a irnproved disease free srm'ival, respectively' with. the. addition
of paclitaxel to AC. thotrg& only cALGB showed improved overall survival [5;6]. The redrrction inlrazard
for recruxence and death rvere 17% and l8016,. respectively, rvith. the addition of paclitaxel h CALGB' B-
2g similarly shorved improved drsease free suriival of l?% though ovelflll survival was not differeot
betweq anns with agd without paclitaxel. subsequeut studies, e g EC!! ll99' emplgred goryrariso[s
between *--klt;;d ."*ry 3-*-;i ;#;e 
fbr paclitaxel or doc*axel following 4 gYctres of-Ac worueo
with uode-positive or higXr-risk node-negative briast cancer [7;8]. Ttrere w:re rc difftreuces behree[ the
raxanes. A* ";;d; 
toivery trrr**-**it paclitaxel. si8n,fi".ult$ iruproved overall s*rvival was obsewed
i* the s.oup receiving rveekly paclitaxel (HR l.:r;'fr.Ot) that was lrot evident in the sotrp receiving
docetaxel every 3 weeks (HR I ti; pro.t; even thougilr every 3-week docetaxel showed better DFS'
Siruilarly, c*b,q*r which- *"utu*rca *oro* with nodJ-uegative bteast caxlser and at least one higlr-risk
factor for rec*re*ce (trunor size > 2cm, negative honuone rlceptors, tumor histology ggade 3 or ]" or < 35
years), deuronstrsted a sippificaut i*pro*ii*t in_disease &ee surviv*l iD tlre taxa0e-cofltai{ing TAC arm
(docetaxel. doxonrbicini*oc *y"rnlrhospharnide).o"-*t the FAC amr (flxororu'asi1, doxorubicin' and
clclophosphamide) with 87.896 *a st.t%, respectively (HR 0.68.; 95% cI0.49-0.93; p=0"01) thougfl the
differe,ce i' survivnl rates rvas ""i riri*r"aut [gi. In studies compariug docetaxel adruinistered
-B-

5ffirubicinandcarlroplatininparientswittrEP-PR.HER2uegativebrea$tcalrcer(TNBC}
concurreutly or seqne*tially with doxorulricin. there wns fl trnnd toward superiority of AC x 4 followedby
doceraxel x 4 (AC=*T) as courpru:ed to TAC x 4 iu ovsrall sruvival and Ac---rT wae luperior to TAc x 4
fbrdiseasefreesundval(p=0'006)[10]'However'BCIRG005'acourparisonbetwee$TACx6to
seque*tiar ac-* + tuo**iuy uo**tu**t x 4 in lvomeil nith nodeiosltive' tmR2 uegotive txeast cancsr-
showed uo difference betweeu the two regimens for DFS [lli. overall, the majority of patients ou all of
these ftials had the most coriu]}on strbtype-of breast .un*.rr ho*rCIile receptor poritive disease'
?,3.2 Rationole For Use a{p;;tinuw-Based Chewor*erapy For Tke Trestment af Patients Wirh TNBC'
Tlre tr.eatrnent paradigur in breast "*"-t lt *.rot r*g ftu* an empiric uppt'o"ch to a urcre targeted one in
whic.h * p*rtifia, brirt ****, pu**typ* ls iaeofi{e* tlrat is *oo ut"ty to respoud to selecJ eombinatiou
regfuneus of targeted agents ard chemotherapy'
Breast cancers are represerted by a heterogenous-gtrolrp of fumors, characterized by a lvide spectnuu of
clinical, p*tSologic and molec*t*, i**tir"uTre-r+]. rr.ir wicle spectruur of factors accorurts for v*riations
inresponse to ttrrerapy "nd 
out.ome* r*org ***"o diupo*"a wittr breast ca$cer [15-17]' Routine clinical
variables snch as prinrary hunor size, uodil stahrs, ug;-*d honuoual receptor stahrs have rnore recently
been romplernented by nrore extensiv, urolec,rl* profiliog in au lter-npt to refise proguosis and response
to therapy [ls-?U. There have been rrlrrerou$ reports deniusnatiug that breast huuors udll segpegate into
prognostic categories based on hierarchical cluster *ttyui* of gerie exprcssion profiliug [12;15;20-25]'
These unique molecular prtt*rr, ** help guide cliniciaus regardi0g both progrrosis and response to
therapies,
More recent attention has beeu devoted to o classilication systemrvhich eruploystluee corumonly available
ruslecular markers, e$trogen receptor, progesteroue receptor and HER? andelassifies patients ir:to srrbtypes
(Luminal, HER2 and Basal) 6rl;rrii;zil. r*"i*l strbtypes *q:-:** lrsmrone receptor expressing
tru*ors ad carry a fayorable prognosis" These tuuors have g*re expression pattems which are sirnilar to
the ltuninal epithelial .o*pou.oiof tlre breast aud genes issociated with estrogen receptor activation'
HER2 subfypes refers to the group of honflone receptor regative !u}}op with a specific geire expression
pattem. Althoug& not all hunors *[i.r, *" Hrnz posiiive by cliuical te*ting (iunnuuohistochemistry and/or
fluoresceut i, situ hybridizatiou) stricrly falt into this category, most HER] positive hrmors rvould fit this
criteda [13;17;?5J. while these runrors are generally r*""ptoi negative aud c'arry I poorer proErosis than
luminal t1ryes" the effective$ess of trastuzuriab in HER? iositivJpatients ca$ significanfly imp*ct ou the
outcomes ofthese Patients [27]'
Basal-like t*mors lack both honlole receptor aod HER2 expression,. and tlespite h*ving a199r grosrosis'
these h**ors liave been showu i" r-"-*iri"arrt shrdies to be'respousive to.cliemotherupy [13]' Basal type
funrors have been shown to be more agpressive. are ruore conrmotly seeu in African Anrerican wornen' in
you*ger woruer> a'd are .oooooJy ;;;; * lyom:n *lro o= BRCAT csn'iers [13;15;2312s:29]' while this
classificatioa system is based oo it * more compt*" a"d exteffiive g*netic pronting a$sflys! tbe siruplitied
method of classilieation based o,, it " 
universaliy available aud coi"'o[ly eruployed ER' PgB' and HERS
cli'ical assays rnake this system aptealiag *no "rini*ally 
trsefrrt. Accordingtry. cliniciaus are utilizi[g the
combinatiou of ER, pgR and HEHi to clissi$ patientsLto th*u* subspes and are increasingily ftilizing
..Triple Negative,, (ER-, pgR-, **-l 
in clinical decisiofl making and protocol desigrr. Data usitg urore
extensive inuu**histochemical staining and gene pror-rii"g shrdiel have cleuronstrated that these "basal-
like., cancers are more commonly positive ri Heir exprJssion, basal cytokeratius and c-Kit [l?;18:23]"
-9-

These ..,nor$ also are characterized by low erpression of BRCAI aud this phenotype is couulou am0ug
BRCAi ca$iers ond spor'*dic hmrors tiiat reseuible tumors iu BRCAI caniers [28J.
The TNBC dexisrration arises from the lsck of knowledge beyand 9gn1eu$onal molecular feahues
regardiug specifii aberrations giving rise to this breast c&ocer subtlpe and its biologry- Cytotoxic agents are
tui'rruinltuy for treatrueut ofpatiints with TNBC given the sbslnce of targeted therapies such as the
horuroual rn*nipulation and HERI,-directed tlrerapies used {br horrr:oue receptor or HER2 positive fisea*e,
respectively. Adjw,a*t atthracycline-based regimeus plus taxane* substantially reduce the risk of breast
csncer recu*eilce a1d denth initrding those vriih at least oue hip{r rirk factor for recurrence, e.g' turnor size
> 2 cm, legative honnone receptors, kgh $ade [3-9;30]. However, a paradox lras eurerged tlroug]lclinical
trial observatious. While TNBC demonstraLs higher pathologic complete respon$e (pCR) with
ueoadjuva,t chenrotherapy as cornpared with non-TNbc [3U, it still displays worse outeomes suggestirtg
need for more e{bctive iherapy io er,adicate hrmor cells. Tlre potential benelit o{ plalimrur- salts for
treatment of TNBC is emergingirr-:rl. BRCAI-deficient breast cancer, a sub*et of rNBC, is known to
be sensitive to double strutrd break-irrdtrcing agents, e.g. platiurun salts. However, platinums are not used
ro*ti,ely i* the treatrnent of patients with tieast .*rr."i'. iinkr b.tt"een the pathogenesis of both BRCA'l-
associated ad nonBRCAl-associatecl TNBC subsets lmve renewed interest in the potential benefit of
platimrm'based tlrerapy fbr TNBC.
platinati*g *geuts bave beeu urder ev*luatiou for use iu the treahnent of patients with early stage.breast
cancer as mofiothetupy rrot also ir combi*ation with oiher chemotherupeuti* agents" These strtdies are
sum*rarized in Tabte-i. Iu a proof of concept neoadjuvant study, monotherapy_with cisplatin at 75 mg/ruz
every 2l days for four cycles in patients with stage-Il-[I TNBC demoustrated a228/o pCR lte and 6490
clinical complete o, purtlut ,*r$rr*. [32J. Beuefirs were similarly observed using cisplatin for BRCAT-
associated tugors and with the combination of cisplatin aud bevacizuurab fur TNBC [3a;35]' Gepllstlto
evaluated addition of car"boplatin (AUC ?) and beiacizuurab to paclitaxel phm.liposornal doxonrbicin for
TNBC []6J" Additior of carboplatin resulted iu an additioual ?0% iucrease iu pCR over that wit]rout'
Howev&, carboplatinwas discoitinuedinnearly 5trr6 due to its toxicity infhe coutexJ of this multiple drug
desigu. promisiug results with platimrm *g"oi* has led to the developnrent of several st[dies for the
treat$reot of patients wiflr mrgc an#or bncetlz un*ation-associ*ted tuluorB: neoadjuvant weekly
po.tito*.t plrrs agtlya*y"tio* autl cyclophospharuide, r.vith cr without cafboplatin, aild with or without
bevacizumab (CALGB a0603); adjuvarrt cispiatin wirh or rvithout the PARP iflhibitor nrcaparib tor residual
disease after staldard n*o*di,r"*t therapy (Hoosier oncology)l neoaduvant authracyclile -aild
cyclophosphamide follorved by paclitaxel'or geurcitnbine plus 
-inrboplatin-.for hrurors with a higlt
rrl*orogo* recorubination deficiency score {ECbG 5t 12) [3&]. However, tbe disadvanlage of these shrdy
designs is that ttrey e-thei utitize u uigir.r n**ber of cytotoxic agents with gu'eater risk of side effects and/or
utilize a potentially less effec.tive doJe ofplatintun" Tiruru data support optirnizing the use ofplatinurn salts
in the treahuent of TNBC tlrouglh rationeidesigu. However, the optirnal incorporafio[ of platinatilrg agents
iuto the treahueut of patients wlth ear{y stage triple uegative breast cartcBr is not yet knowu'
-10-
and carboplatin in patients u,ith ER- pR" HER2 negative breast cancer (TI{BC}

eut of plti*nt* wlth tdple negethe
r 
pCR??%
r 
cCRorcPR 64%
Neo CDDP ?5mg/rn:q ?l days x 4 cycles [32]
r 
pCR 909t'
Neo CDDP T5nrgJmtq 2l days x 4 cycles [34]
r 
2696cCR
r 
S?%cPR
r 
1196 $D
o Zo/vPD
Neo CDDF ?Smglm2q ll daYs x 4 cYcles
+ BEV 15 rug&g q 3 $'seks x 3 cycles p5]
additionalpCR of 20% with CARbut
reduced CAR dose due to side effects
Gepanixto [36]
CAR (AUC ?) + BEV + WP + IiPcDOX
r 
pCR"af369i overall
r 
35o/s hr thss€ wi& BRCAII2-TNBC
Stage I-III
BRCAI/3 hrmors
kEC0G 0105
NeoCA,R(AUC ?) + GEM (l000urg/m2) + IN (s.5
r Preliminary datal ueutropenia.
tlunurbocytopenia
r AdditiT,e effects CAR + BEV:
r 
pCR (breast) 60Yo
CALGB 40603 (ALLIANCE)
Neo WP (8Ornglmr) >>,qNTHR + CTX* CAR
(AUC 6) *BEY (10 rngikg)
Corubination superior to control
51% (38-679/0) I's 24% {94396)
TNBC >2.Jcrn if
palpable or >?crn bY
irnaging
r-sPY 2 [3?]
Neo lvP (80 mdr#) >> ANfi{R+ CTX q3'3weeks
*A8T.888+CAR
BRCAl/3 fi;rnrsrB
Residual disease after
standard ueoadjuvant
trBiltlue$t
Hoosier Oncology
Adj CDDP* RUCApARIB
TNBC: BRCAT/3
tunors
hruror$ witlr high
homologous
r€cox*klatio$
delicieucy score [38
EC{IG 5l ll
Nee ANTIIR+ CTX th.{t p or GEM (1000tnfl1d) +
CAR(AUC2)
anr. CDDP: cisplaiin. C-dR:. carbo,platin,
GEM: gemcitabi$e, BEV= bevacizunrab. DOX: liposornal doxombici$, Fpaclitaxel. WP: rveeklY?ac1ff:lrY:::tl;":
ANTHR:anthracycline, CTX.=cyclophosphaniae, iCn: pathologic courplete response. cC&: complete clinical response' cPR:
. .{UC : area rmder tbe cunlq'glo1g
HffiHonrbicirrartdcar.boplatininpatiantswilhER.pR.HER2IrBgati1.ebreartcaltcer(TNBC)
B"atianale For combins,tr,rtd Th*tp1t with Anthracyctine A*d carboplatin- frrlgcrs cascer Institute
of Nart lerury Clinicat Experience w*n r*, (ombintation o{Liposomnl Doxorubiein And Corbopl*tin
iar The Treatmext af Potients With Triple Negative Bress/ Cancer.
preclincial and clinical evideuce deuronskate tliat loss of BRCAI fiurction. as occtu'$ in BRCAI-associated
breasl carcers ard i1 at least a subset of triple negfftive breast cancefs. predicts response to select
cheruothernpy including platinun-based conrpourds [32;38]. Moreover, as prior preclioical sfudies
suggested the combiuation of cl.totoxics with bevacizumab to be syuergistic, this led to the inrplementation
oil pfru** Itr trial of rveekly paclitaxel versus rveekly peclitflxel pltx beraciannob as first liue therapy for
2.4
ll
Sfrrdv nesisn
?opulntion oI INtsC
Ktsult$
Stage II-[I
BRCAl trunors
TNBC
{pa}pablet'mearurabh}
Stage II
Stage II-UI
a
a
Purding
Pending

Title: A Pha$q
doxonrbicin and casoplatin in patianis with E& p& HER: negative breast ca, cer $NBCi
locally recurrent or metastatic breast cancer (82100 htal) [40:41]. As an iruproved 5 nronth pfogression
free sruvival *ud response rate wirh the additiorr of bevaciztunab to paclitaxel was obserred, this provided
a rarionale for pifoti"s tlw conrbination of doxil (DOX), carboplatin (913]. *d bevaciarmab (BEV) in
patielts *itfrpr*"iou*fyuntreatedpatientswith rnetnstatic ER, PgR, nndHER? negative breast csncer. We
condueted a phase I/Ii irvestigator-iuitiated trial at the Rutgers Cancer Instit[te of New Jersey in 31
patietfs rvith previousiy rurrreatid TNBC [unpublishedJ- All patierrts had rneasurable disease a[d an EC0G
pS < Z, a6d adeqrrate 6oue rnarro*, ,rrr"lirod hepatic hurcti,ou. Patierrts received DOX (30 urg/[r2), CAR
(euc 5) and rr:v 1rs mdm2) every 4 rveeks. Dox rrur selected as the prefered anthracylile given the
reduced cardiac toxicity *ira oo*po*t le efficacy of doxil versu$ doxonrbiciu repoded in a phase III trial
iu wonren with lretastatic breast crurcer [4e]. Crade 3 non-heuratclogical toxicities inchrded: hypefieosion,
fatigue, snd lrnnd-fCIot skin reactior. Grilt- 4 hematologieal toxicity incl$ed tluombocytopenia- No
siSlieaut chauge in cardiac fiurctio$ w*s observed aruoug tlre first 6 patierts emolled iu the phase I
po*loo. Atopecii was not observed. Of 30 evaluable patients. 80% had eomplete, partial. or sta!! disease
at 6 ,ronths *itt t I rcsponses lasting 6 months or longer. Medinu overall sruvival (os) was 10 nrouths
where 15 patients w"re alirr* at l0 nionths or longer. Foor *"r" uot evaluable for OS drte to reloeatiou'
These results deuronsh-ate that the conrbirmtion of DoX, CAR. and BEV is au active and well-tolerated
'egirne, 
iu previously untreated TNBC. Bevaciauuab contritruted little to the activity of this regiuren *nd
rvas discontinued in a nurnber of patients sec.ordary to bevacizuurab-relnted toxicities- Subseque0t data
suggest no benefit of bevacizuruob iu tt e tre*tment of patieuts with lrresst earcer including TNBC [43]'
Cotiea er nl [44], the ob.jective response late for the corubiuation of pegylated liposomal doxorubicin at 30
rudm2 and cortoplatin,?ay I of each 28-day cycle" was 3196 regardless of taxane pretreafineDt- Taxane-
nahe (u=41; 12 were ER,1PR-) and taxaue plekeated pafients (n=42: 20 were ER-/PR-) had PFS of I aud
5 months, respectively, with excelleut tolerability'
z.tJ Use a{Liposomsl Doxorubicin In The Neaadjuvanl Setting For The Trealmcnt of Potients Wilh Brcasl
Cancet
Liposomal doxorubicin lras been used in &e treatrnent of breast carcer in the neoadjrwa$t setting. Selection
ofiipasomnl doxonrbiciu has gaiued favor due to tbe lower deggee of toxiciry, includiug cardiotoxici8- as
courirar-ed to colventiogal JoxonrSicin lvhile retaining siurilar efficacy [45-47]' Multiple*sfudies
demoush-ate its safety and tolerability alone or il combiration with other cheruotherapetrtic agents. Because
skig toxicity of iiposomal doxonrbicin includes prurinu, nraculopapular rash, palma}plantar
erythrodysesthesia and rarely Stevens-Johnson syndronre, its safefy in tlre rrcoadjuvant setting has
pr*lnuiy been rsised. However, review of the literatrue has rot rev*aled issues of poor worur! healing
a&er surge.ry. pegyl*ted liposoural doxorubicin at 20mglrrf was used ilr combiuation with
cyclophosphamide ur pr*op"rotive beahuert for patients rvittr locally advanced lxrast caocer where it rvas
giveu every 2 weeks for eiglt doses [48]. In this rtrrdy: definitive breast sugery was perfomred fotu r'veeks
aller the lasf dose of liposJmal doxonrbicin on all patieuis (13 breast-conservi[g surgely; 13 urastectonry'
and i,cluded either *"otin"l lyruph node biopsy in six or courplete axillary- lyruqh node dissection iD the
nrajority). Trect$eut *"* uu"fl tolerated. *ittr rro grade 4 toxicities, and had grade 3 skin.toxjcity i{ tluee
paiie.ts and hand-fioor syrdrome io four patienis. No docruueutafion of delayed srugicll healiug was
repofied among t1* SAEs. ft" su*ty of tt. courbinntion of neoadjuvant paclitaxel 175 m$nr? aud
pegylated liposimal doxorubicin 35 mg/ru: every three weeks for six cycles was evatuated in 35 patients
wi,th locolly advalced br:east csncer 1+i1. Xrtrite the prirn*ry toxicify was.skiu (grade 3 in 1ly.o bcfudiug
pahnar-plantrr:*ryf""Oysesthesia i" bvri. Altbough treatruent was discsutiuued due to skin toxicity in foru
patielts, it did uot impede surgical healing aftei mastectonly. A similar study was uudertake$ for this
neoaduvant cornbination leadiug io br*ari conserving *r,rg.ry iu 55% of patie[ts which showed the
-12-

Tirle: A phase I trial of liposoural doxonfiicur and cnrboplatin in patielts with E& pR- HER? IrBSntive brea$t ca*cer (TNBC)
I-I
combiuation wa$ sctive in opemble aud locally advanced brerst cfl$cer rryith a ulaangeable safety profrle
[50]. Only four of ?? patients expedenced either grade X or gracle ] lraud foot syndrorue' To explore the
activify of pegylated liposomal doxonrbicin (PLD) as neoadjrwaut therxpy of breast csrcer, it was
conrbined ,uitd'*i*pru*i *,r iufusional fluorotuacil tccn for I cotusts in pntiefits \4litb primnry ot
recurrent T2-T4a-d N0-3 M0 brcast cancer iucluding ER+, ER- (n=l), and rruknown ER stanx (n=9) [51]'
No adverse events on worurd healing reporterd aud ciinical re$ponss rate was 77 -5o/o. However, as only one
patient had rNBC and the mnjority-of itrose with unlsrown ER statue would be positive for expression of
ihe receptor, the dats carurot be extrapolated to the TNBC population for clinicnl response'
2.4.1 Key Obsertotions trn The Uxe Af Pfutiaaffi-Based Tlterapy For TNBC" . - t- , ---- BD- ^ r ^-....
Faltors pr"rriouuty showu to be-associafed with good cisplath response include low BRCAI expressron,
BRCAI prouroter methylation, aud p53 urrru.iu* or frameshitl urutntious (NSM) [3?J' A significant
associatiCIn of trulor psi Nslut with cisplatin response was uoted though this did not exclrrde BRCAI-
Butant fllmors. Furtlrennore, mgtationnl'sta.tus of other geues wss uot evaluated [33152]' P53 expressiou'
as a stnrogate for mutntion stahx, as a prcdictor of cheuro&erapycutcoure has ffd9le! v-uiabl"e results
[s3-ss]. ru** p*lgliug of gedgt **thyt*tioo stahrs from patierrts tr:eated rvitlr high dose platimun-
based or.ooo.rrional clienrotherapy shCIwed improved reclurence &ee ancl overall survival with platifltun
for patienfs with tumors char.acterized as BRCei-lik* ** corupared with non-BRCAl-like hrmors [33]' As
o*ly z:oro of assessable hunor.s had BRCAI urutation and 3bo;a of the vgslirrirrg assessable turnors had
gnbat methylation, this ideatifies at least a subset of nonBRCAl-associated TNBC that is also platinurn-
sensitive.
Additionally, residgal TNBC followfurg neoadjuvurt therapy repressufs a urarker far high risk of dista[t
relapse *d poo, outcome [reviewed l" :g]. Up to 30% ;f p*ti*ot* have residrml disease at the end of
ueoadjuvapt cheurotherapr [60]. Gene expresiion patterus, basal-like breast cailcer stafl$, apoptotic
mar.kers, and prolifbratiori scores of this residual <lisease corelate with shorter reclu:eflce fiee survival
[60;61]. Understanding markers tbat would predict for resid*al d^isease would potentially lead to clirrical
trtal desigrr to ir:rprove-clirrical outcomes in TNBC. Current feasibilify of huuor geuoruic sequercfurg offers
a novel *lrpro*.h to identi$ genouric dteratious that r:ray not orly predict tbr responre but wiu inform tlre
design ofnovel ther-apeutic or targeted approaches and drug development, poteutially leading to i[rproved
or$conres for patients with TNBC.
2.5 Ntxt Gsn€rstior,segnencirg (I{Cq Of Tumots From Patients With TNBC'
Feasibitity of next g&eratiois*qu*o"iJg on tumol tissue has resulted in ideutification of ttuuor unrtational
landscapes in multiple hmror types. ThiJprimary identification has provided laluable iusights into genomic
alterations that inrp*ct ou t r*orig"o*sis'specific to tissue types arrd cancer subtypes" The next generation
of studies such as this study tiltt oi* io dptenuiue &rnctioual sipinificance of speci{ic mutations on
progposis, as predictive rnarkers for response to couventional tlrerapies, as predictive m*r'kers for response
io fiigeted agents directed at actiouabli nrutations, and as a gnride tbr the development of futue cli[ical
lsiats g6s$irring targeted agents and/or c1'totoxins.
Genornic pro{ilirrg 5as catalogued umtational landscapes in trunors irrcludi[g lxeast caucer wltere fhe [rost
cormron snuratiJunrtations fu TNBC are TP53 (54-86%) and PIK3cA (10-21%) with other-&equeflt
mutations ,rri*lriy obserr*d iu sbotlt loYo of TNBCs [62-6a]. Although this has provided valuable insi$t
into genomic alteratious preseut in specific brgas! cancer-subtypes,,outcomes or responxe to specific
ehe*rotherap*di; ogeots have not been systematically ev*luated" llhole geuome sequeficiltg in nretastatic
- l-1-

doxonrbicin and ccrboplatil fur patiants with E& p& HER2 negfltive brcast ca, cer (TNBC)
INBC has revealed potegtially actionable molecular *lterations [65J. Next $ereratior $equeocillg of pre-
tr:eatment biop*ies *oru patieuts with TNBC receiviug neoaduvant treaturent with doxo'nrbicin pl[s
cyclophosph&d- r"lu*uua a s$ghtly higser soustic runtation rate lxr fuuror nnd siSrificmtly hig&er
fuq,r*o*y'of mutatinns in the elri*ptitiAylinositot sign*ting pathway ry ryryots from no[}"respfirders ss
*o*p*.i to responders togl. nrutle-rurore, hl patisnts 14.ith TNBC treated rvith neoadjuvant chemotherapy.
a,rplification, ni.ru ,r*o.iri*,l with enhanced gene expression aud alterations in DNA repair also ide0tified
o.ulrgroup with poor recurrence free suwivat and overall sruwival [60;5lJ' It is not ]:rowu if the sanre
mutations wotrld il prefictive of response to platintuu . There{ore, the emerging technolog; .a{ genomic
pro/iting may identify genomic dreiations piedictive for drag respot se ond inform the design af novel
th*apeutic or targiiei approaches lo actiansble mutalisns to improre a$tcames in TNBC'
2.5.1 Oarllrp erienee With Turgeted Next fienerstion $egaencirg OtfNBt'
we have demonstrated or:iability to procure aud perfonn genomic sequenci0g of tuurors tlrough an IRB-
approvedprotocol ns part of fhe irutgers caocer tnstitnte olN.w Jersey Precision Medici0e lnitiative (PI:
d*.r*; sub-investigator/supportiig scientist: HirshJield). $/e have suc,cessfully recnrited 100 patieuts.
have perfonned clinicat g*4. r-lci of funrors using the Foundationoue platfonn fronr Formdatio0
lv{edicine to identify gu;*i. alterations (nrutations. copy nunrber alterations, insertitrns, deletions.
rearrangemeuts) in roighly ?40 cancer-re.lated geues. We also hold weekly tnqgt bryr{s to make
ysggmrnendations for tai#e* therapies based nn*thos* profiles" Orx' gsoouric profiling of niry TNBCs
reveals an ayerage of 3.?ilter*tioor p*r tumor ineluding frequencies o{1!* following gene alteratious: p53
ggo.1o (3 00n***i, 1 splice site, 4 rni'ssense), PIK3CA i30r6, NOTCH 33*6. PTEN ?3%, FGr',#GPR 22016.
h{yC ??Yo [rurpublislred]. Tluee of lhese TNBCs were fi'ottt individuals on our DOX, CAR' BEV sndy'
Of these, Hro trad serial spcimeu NGS and revealed urutational gain in at least one gere over baselifle'
2.6 Supporting Rationale
nypottresis Specific sets ofgenom ic tberrCItiaas ord CIsso ciated wiih paor rs.str ottne of triple ncgdtive breast
c$flcer to eheno$r*apeutiis resxlting in treatment {oilure and poor c{inical oiltcames. Proliling residual
TNBC after neoadjwa$t chemotherafy will identi] ruolecularly targetable lesions in the chemotherapy-
resistalt 
"ooqpon*rrt of the hrmor and provide testaLle hlpotheses for dnrg targeting and therapeutic kial
desigu for mfgc. A neoadjuvaat regimen of liposoural doxorubicnr OoX) and carboplatin (CAR) followed
by &finitive surgery and iveekly pa"clitaxel (wp) ror sfage II-[I TNBC is being mrdertake[ a1 fhe cliuical
setting in which io test these lrypotheses. Hipilrer risk stage I TNBC patients that ruay receive cheruotherapy
perNCCN guidelines uray also be included-
Although the breast cancer death rate bas decreased sisce 1990, neady 40:000 US women are expetted to die
fro,r itln z0l3 tli" worrr.n with triple negative breast caucer (TNBC) stitl bear a disproportionate bruden of
the morbidity anO"mo*ality associ"ied wiih this disease [2]. Giveu the known statistics, novel approaches are
clearly needecl to gnderstand the basis for these ob*ervations auti to iurprove oufcomes for women with TNBC '
The TNBC desipratiou arises from the lack of knowletlge beyorrd cs$ventioual molecular features regarding
specific aben;atiirrs giving rise to this brenst caneer subtype and its biologry. As these cflncers lack expressiou
oi gn or amplific.*iiou oi HER?, rhere is no effectir.e targeted therapy. aud systemic therapy of TNBC
currently relies on the use of ctr(otoxic chernotherapy. However, a paradox has emerged. Despite-overall worse
clinical outcomes, several studies deuroustrate higher pathologic compiete respoo$e (pCR) rvith neoadjuvant
cher:rotherapy iu TNBC as compared with nou-TNBC. Those achieviug pCR have excelleut long-tenu
outcome, rvhile those rvith gross resi&r*l disease (GRD), particrilarly those rvith specific gene expression
14-

doxonrhicin and cartoplatin in p*tients with E& pR" HERS neg-ntive breasl cancer (INBC)
Tille:A
2.? Avsilsbility of Doxil
When there is a shortage of liposoural doxorubiciu at the
petterns) epoptotic merker$, and pr:oliferntion score$' have n very poor proslssis [revierved iu 59;60J This
suggesis tlult TNBC are heterogetreolrs and that a subset are seusitive to standard chemotherapy. In keepiug
*iii thir, a subsef of TNBC also appears to benefit &om platintuu-agents, with}iglrer resporse.rate being
associated with p53 *ot*iloou t3l-3i1. This leads to fwo very iurportaut cfuric.a] challeuges: l) identtfyiug
which TNBC will respoud we1io staldard chemotherapy aud platiuuur, and 2) ideufiffing novel therapeutic
nhafegies for those *&.ur* that do not respond lyell to ihese afeuts. Ctu:rent geuontic sequencing tecluriques
rnake"feasible a hypotlresis-driven *pp*u.t to trcth findpredictors of respon*e to neoadjuvant clremotherapy
and ideutify potential targeted therapies for cancers thet fail neoadjuva*t therapy"
Staudard neoadjuvant cheurotherapy for palients with breast cancet cousists of anthracycline plus
cycloplosph*mide (C'Ih-) followecl Ly' tu*"rr*. However, pharuracokinetic properries of CTX ar"e not ideal for
TNBC as one of its naip active ruerabolites is in equilibiirrm with its taufolner. aldophosphauride, which is
oxidized by aldehyde dehydroge.uase (ALDH). The increased ALDHI expression observed in TNBC is
corelated with resistalc* to trx tgl-ro]. Frutlrennsre. previous data hnve lead to the derigu aud
i*rplementation of several shrdies fuI the "triple negntive popuiaiion" utilizing platinum based regirnens' The
trial desigus, however:, are based on sddiiion oi ptatinurn ogents to existing drug reginrens which has
previous$ resutted in increased toxicity aud/or discoutinuation of platkuur agent-_The corrrbination of Dox
and CARhas beeu shown to be a well tolerated and active regiruen in patients with advauced ovarian carcer
1lf -r01. Therefore. we now propose to use carboplatiu ns ari alternative to CTX in an anthracycline-based
iegi$en that has demoastrated "ffi.*"y 
and excellent tolerabilify in the treaturent of patients with other tunor
du, ura ir the settiag of uprastati"'ixgc [44;?l-76; rmpnblishedj" we prop,ose a neoadjut'aut regiruen of
tip*uomat doxorubicii(Dox) and carboph&r (cAR) then definitive sugery followed by weekly paclitaxel
ffi) for t5e treaturent of ear.ly stage TNB-C. Early stage breest cancer is defiued as stage II-[I for the puposes
of tfri, study. a. weekly p scheduli wilt be used as it impruves disenre-free and overall surival as compared
to every 3week paclitaxel regardless of receptor status and has inrproved tolerability [77].
Our prospeetive clinical tri*l depicts a well-tolerated therapy incorporatirrg carboplafin that could be nloved
into i5e edjuvant setting" aud has little risk of hair loss, a profile tbaf rvould be palatable to yourger wouten
with TNBC. It wouldile expected to be *tfeetive for nnC,q.tn associated nmrotB and for tumors with
rorserse or missense mptations in p53. This trial seeks to strbstitute platintuu for a standsld agent i.a
cycloplosplamide" which is predicted to be less effeclive for TNBC. We propose to utilize genomic profiliug
i" tfr* settipg of the clinical trial to conrlate profiles with resporme aud to validate a ther*peufic approach
based on the gelomic profile. Geuouric analysis of TNBC may idettiS a ruutational laildscape that reflects
huuor biohg! and/oridentifies an actionat{e u}utation for which targeted therapy coulct-be applied- As
ildivi6uals frtl, gro** residual disease following neoadjwant cheurotherapy have- high risk of distant relapse.
existiug urutatiois may offer predictive valueln &osi likely to relapse as well as what therapies may be
effective. patient-deriied xeaogr:afts {PDx) from patieuts with gross reridual disease will model each
individual trmror" rempitulating-iU" .*iq* r:rutatious found iu tlreir turffrs and the genetic milieu' PDX and
e$ yrvo assay re po*u to up"iifi. thernpies may infoim future fi'eatruents likely to bene{it to a pafiicular
patient at the time of their'ri*pr*. Thereiore, this protocol could shed light on not only effective treatmett of
prinrary trunors but also tlrat for recrrreflt disease or tlistaut metastases-
nts will
*c- 
---a----
be allonred to receive';eannent with epimbicin, an altemative anthracycline. Neoadjuvant treatmeut would
then colsist of epirubi.ir, (OO mglurl) and cartoplatiu (AUC 5) in patients with ER, PgR' HERz uegative
-15-

Title: A phnse 2 trial of liposouul doxonrbicin ald calboplatin in patiarts with ER- pR. HERS lrBgadve breasl cancer (TNBC)
I-I
breast cflrrcer. The patient rvill continue to foliow all requirenrents pet protocol gfiideliues' This protocol is
to prtoritize availabie liposomal doxanrbiciu to those patieuts for rvlrour there is cmafive interrt. lessening the
possibility that epirubiciu will ueed to be used fbr this cohort.
4.
Experimental Ilssign snd h{ethods
rhi* is an open-l*bJ, ph*** tr triat to determiue tlre rate of pathologic complete response from the treatment
of patients *ith ,t*g* [-m, ER, pgR" HER2 negative brecst saucer with doxil and carboplatin- Higher risk
stage I TNBC patieits rvho"mryreieive chenrotlierapy per NCCN ggidelines are also included. Patiente will
be e,rolled to receive the following treahnent: * cycles of neoadjrrvaut carboplatin and liposoural doxonrbicin
aduinistered every lg days (car.6pktin AUC 5. liposorual doxonrbicin 3oruglm!) followed by deftnitive
ur**t surgery andihel tz weeks ofweeklypnclitaxei (80 mg/uf), Definitive breast suryery willbe performed
tro sooner than four weeks &om the last dose of liposomal tloxorubicin. Patietts may also-receive additional
therapy. e.g. adjnvant radiation fherapy, as clinicaily indicated at the discretion of the keatiug physician-
Secoudory endpints will be detennined aad include: re{urrerce free stxvival (R.rS), 2-yeor RF$, an{ overall
stnvival (OS), ihe mutational spechum of hxnors *nd ttreir *ssociation with response, and in vitra and ex r-rvo
components fo, fi*"tiooal pre&etion of &ug respouse based on mutrational landscape to inform fufue therapy
at time of relapse.
To cssure cardiac safety of the combination, initially six patients rvill be eruolled. Assetsment of cardiac
frmction wil be made after 3 cycles. Lf one or more *r*** of cHF are observed accnml to the study will be
stopped. Sixfy patieuts nre expected to participate in tb.is {ive year study. C}inic*l follow-up will co[tinue up
to twenty years following completion of thempy.
Patir.nt Selection Criteria
f.
5.1 Inclusion Critcris
.A patiert ir eligible for enrotrlmpnt if *lI of the foltorring inclusion criterir tre nret
5. t , I $y'omeu with previouely rmtreated, uuilateral stage ll-ttl breast csrcer, ERIPSI HER2 ryfative
(ERESgo, fgfisso,a, HEXZ &1+ by IHC or HSHS?"0 or ER55o1o, PgRS?09o, HER2 0-l+ by IHC or
HSHS2"|) Io"fided by stereotactic biopsy, core biopsy or excisional biopsy (gtttA inadequate)-
Stage I **y U" inchdi if cliuically o*guti',r" lymph nodes and tumor size is a miuimum of 1.0 cu.
and tunror is identiliable wrder office-based ultrasound guidance. If ER and HERZ are negative,
PgR<2Mo allowed'
5.L2 Age:"18- Nn uPPer liruit.
j.1.3 Nigative serum or urine p-hCG pregrnncy test st screeri$g for patientx of ehild-beartng potential
rvithiu 1 week prior to mrollueut-
5.I.4 patients wiflr reproductive potential must uss a$ *dequate conhaceptive mEthod (e.g' abstinence,
intrar*eriae device, oral contraceptives, barrier device with spennicide or surgical sterilizatiou)
druing treafiueut and for tluee uronths after cornpleting heatrneut'
5.1.5 Patieuts urnst have an ECOG perfonuance sfatus <2 (Appendix A).
i.1.6 Life expectancy ) 52 weeks exchrding their diaErosis of breast caacer
5.1.7 Patients ruust have norurol olgan and luauow fturction as delirred belorv:
t6-

r ANC l 1,500 cellslmml
. 
Platelets I 100,000 cells/$uu3
. Hemo$lobin > 9.0 gldl-
r Cre*tiuine < ?"5 mg/dl
. Total bilirubin < t-5 X upper limit ofnormal (IJLN)
' AST(SGOT)/ALT{SAP! < 2"5 X institutionnl LILN
5.I.g. patie,ts must have nonnnl cerdiac fiurctiou, as evidenced by a left ventricul*r ejection &action
(LyE$ withitr instifrltionsl uonnal limits defined as LVEF grcater tlar 50%. Echocardiogrwu or
I'IUOA *"* *"y fre gsed, but the seme test must tre used tlroughout the sfirdy to evaltrale LVEr"
5.1.g CT CA,p and boue sc*n perfonned withiu 30 days prior to sfirdy ettry alrd does not demoaslrate
ruetastntic disease. PET-CT is allowed *s an altenrative modali$ to CT CAP and whole body bone
scan af the discretion of the treafiug physieian'
5.1.10 patients mcy uot reeeive couct rr*rrlt'trirtrreut with other investig*tional or cffIrmercial agent(s) for
heahneut oftheir breast cn$cer"
5. l. I I The patient must have sigued and dated aa IRB-approved consent form tbat confonus to federal, state.
and institutional gnridelines.
5.l.lz patients must beiligible to rmdergo sur'gery, either lunpectomy or ulastectomy for local freatment
of the lneast **.J. Surgical mirgins'at-dismetion of *'g.oo per {C!N g1udelqes' ryriUw
exploratiolr at discretion of surgeoniut all patients rninimalty have'seutiflel lyurph uode evaluation
at time of,surgiery.
S.l.l3 Imaging ry drrnmoggaur aadlor ulhasomd must be per&nued within 6 months of strdy enhy or
ldnl imagi$g of affectEd b,reast witlrh 30 day* of study elrtry.
5.1.14 Must not exhibit a uon-healing wound ot *y skin breakdowu such as from dental work'
5.1.15 Before *a*i"i*t*ri"g tipo*o;*l doxorubicin, patients mrxt w*it .it-6 rvee*s after surgery as it can
cause local reactions.
5.1.16 Syncluouou ER/pgR/HER2 negafive breast carcers (tuilateral a*#or bilateral) are allowed as long
as at lenst oue foc; nreets criteria 5.1"1 andno ofher exclusions exist" If bilateral breast cancer is
present, then tlre patient mrxt have cnnfirmation of TNBC per 5.1 - ! prior to. treatnrenl. ER/PgR/IIER2
i,egati* influnrlrratory breast eilIcer is allowed as long as no other exclusions exist'
5.1.1? -9r&rnissian ayttmoiscrlpler from the diagrostic AUptl' ond \lyslsilrger!'isreryire!for all
patients.If thJ patient had a diagrostic core biipsy that couirnned TNBCp riar to fhe research biopsy'
tlre pafie,t does not need to **it fo, results oi tir* researclt biopsy to begin protocol ther"apy' Prior
FNA resglts olly are ilsu{ficieut to proceed to chernothempy. If a ptientis undergoi[g a diagnrostic
biopsy witfr p*or fNe onty or inadequnte prior t roly rvhlie ER. PR aod/or HERZ statux could not
be reported, ilre patient must woit foitUe res*lts of *r* dinproetic biopsy.in*luding coufirmation of
breast .*r**r, *O nA" pR, and fiiZ st*tus befqre initiation of protocol therapy- Oaly results for
diagrrostic p,foor** (i"e. coufinnation of breast cancer, ERIPR/HER2 status) will delay the start of
shrdy chemotheraPY.
5.? Exelusion Criteria
A pntient will not be eligible for this study if rny of the following exclusion criteria are met'
5"2.1 $y'omenwbo*repreli$a$torbreastfbeding" 
..r
S.2.2 Secoud primnry -*uligrr**y 
except *oit uit t carcfuroura (s"S- iu situ -earcigrmo nf the celrix,
adequatety reated noa-arelaro**to* carcinoma of tlre skin),-other mnligrrancy heated at least 5
years previously with no evidence of rectxrence. A syncfuonous breast c&rcer is not considered an
exclusion if criteria 5-1.16 is met.
-11-
Phnse 2 triq! d-lposomdd doxonrbiciu
I
urd cnrboplatin in prtients with E& pR" HER2 negative breast cancer (JNBC)
Title: A l
I

ryffinrbicin 
and c*soplatin in p*rients with ER- PR- HER2 negntive breast cancer (TNBC)
5.2,3 D*finitive clinicat or radiologic evide$ce of.metastntic disesse. Luagrns must hnve beeu perfomed
ro greo1*; U*.lO doys (+/- iOuy*l prior to in'itiotiou of chemotherapy'
5.2.4 I{istory of 6ypersensitivity resction$'atributed to a couveutional formutation of doxonrbicin HCL or
tl,ecornponentsofdoxil,paclit'axel'orcortroplatin"
5.2.s serious coueomitant systeuric diru.c*r, (iucluding aclive infections or el}rodc iufection requiring
s*ppressive antibiotics) that ;o*dd;;*p**ir* trrl uJ.ty of the patient or compromise tlre patient's
abitify to *o*pt*t* the study, at the discletion of the iuvestigntor'
S.?.d Myocardial iof*r*t o, .*r*,ii* angiua-*ith'Y.O monthJ before enmlhueut' New York Heart
Associ*tioa (NYI{A) Cfr*u U"o, *,.sC }eaf felfure See Appendix B' uacnntrolled angina' severe
uncontrolled venkicular-.r*r-rrm;, "r*i"-llv 
siguificaut ryiiicar$1at disease, valwla'disease with
docru,ented courpro,rise in cardiac iiurction, or i*ro"u*ograplric evideace of acute ischenric or
active conduction sy*tern abnormalities'
5.2.V Prior antl$acycline, plati0tuu salt, or taxane forLaly *4iEruo"y" within the previotls 5 years'
5.2.8 Xoo*o or a*iu* n*fiutitis B or C lvith abnorrual liver fuuction tests"
5.2.g significant vasculardisease (e.g., *ortic a&eurysmr aorlis dissectiot)'
5.3. I 0 Sltuptomatic periph*ral vascular disease'
5.?.1I Evidence of bieeding dinthesis or coagprlopalhy'
5.?.12 Lrtrinsic luug diseasi resulting irmoderate.to severe dyspuea' 
,,kid0ey,
3.2.13 Hi.tor,-oili"*jot o,.g* a[Jgrsft or condition requiriug cl*gyc inununosuppressro& e'g'
Iiver, ltrug, hearr, bone ruarrJw hanspla,t, or a*toirmiure diseases. This ineludes ffeahuent with
corticosteroids within one uronth (dose of zl0 ;ddsy methylpreduisoloue equivalent) (excluding
inh*led rteroids). patients wlro have received "orr[* 
ir*rrplunt*. cadLer skin' or boue transplants
are eligible-
S.Z.14 N**oriJ*|*tu* disorder {paresthesias, peripheral rnotor neuropathy, or peripheral reusory
ueuropa&y) > grade ?, per the CTCAE v4'0'
i. Z. I 5 cor*ti*ri inri*ould'$ro6itrit adrninishation of eorticosteroids'
5.S Inclusion of Women rnd lllinoritier
The National lustit$te of Health Nn$ and NCI have sfiessed the iurporta[ce of gender and minority
inclusio$ ir glinical services and ,e*earch. Female patieuts accouated for 58olo of eancer patients seen
wirhi, Rutgers Ca**er fnstifun" o;:Ne; Jersey's "i:"i;;t;* 
*t*i" the last year' Of sll female
patients "rt*t*a **11y. Afric.au-Arnerica*s cornprised"?:?%,.tT*]1".* Indiau/Alaska Native 0'2016'
Native Hawaiian/pacific Islander 0-3910, Asians 4-zi/o, multi-racial 4 31:' aud 1'9% Hispanics' For all
patieuts eutering clinical h'ials, the pereefltages w-ere 8?0'6 womeu' 14'796 A&icnn-American' 6'896
Hispanic, ,q,*rri*r* Idian/Alaska r.iuti.r. o.iqro" ili"; Hawaiian/Pacific Islader 0'5?6, m*lti-r'acial
A.2s1o, aud 3. 6Yo Asian'
No person shall. or the grcrurds of age, mceo color, or uatioual origiu, be excluded from participation in'
or be denied thaberefitiof emollment in thin pratocol'
5.{ FarticiPrtion of Chil*ren
parients ,J;; L ,gu of lE rvill be excluded frour shrdy p*rlicipatiot'
5.5 Sources or S{ethods of Recruitment
Pntients will be recnrited throug& the
referral* froru eomrnrurity clinicians or
carcer clinics and tluouglr
18-
affiliate sites. Potential

Title: .A phsse 2 tial of liposonul doxorubicin and ca$oplatin in ptients with E& P& HER: negxtit'e breast calcer (IWBCi
I-I
pafiicipauts will be individuals who present to a uredical or srugical ancologist for treatruent of their breast
cfircer^ Rutgers Cancer Institute oncologists are listed as shrdy irrvestigators. Cliuiciaus will detennine if
the stage anl urolecular feahues of tlrc iodirridu*l't breast ciltcer. based on the patholog rep.o$ ry*:t-+u
ineluxion criterin for shdy participation. Fhysici*ns witrt iuhoduce tlre cliuical trial to t}re individual' If tbe
hdividual is interested i" i"**ir.g more about study participation, the study research nurse will review
ihe srrrdy witl the indir.idrrnl, ,*"i** patient inctusioriard eiclusion criteria, discuss wlrnf is required of
tbe indi;idu*t durirrg participation, *d the consent fiomr. No de{idte tirne &au}e from iuitial diagrrosis is
uecessory so long as pote*ial particip*nts meet sftrdy iuclusion criteria or have any exclwion criteria'
There o.* n* fly*o, intemet use, or physician letters for recruitrnent in this snrdy.
T1e number of patients being soug[t for this *tudy is 60. We anticipale that we will discuss potential
participation with roughly 90 patieuts to nchieve shrdy nunber.
poteltial participants will only be ccntacied once to particip*te in the stndy as corlmeucement of any
treaturent for their brenst **.*, rvill result in ineligibiiity. Coutact for participatiou will occur during the
clinical visit at the time tiuring which heatment options aie disctrssed. A research nuse will meet with the
patient at that tlre tiure of expiessed study interesi aud may cootact the patient by telephone following tlris
Leeting to determile if the individual wishes to pariicipate or any fir*her qtrestions about shldy
participation.
5.6 Study Enrollment Procedures
A copy of the irtstitution's lRB-approved irrfonned cousent docrmrertt *9 E||:ll
ir*gut*t*ry Xiuir. fvf*rg*r and all documents mtxt be received (i.e., IRB approved doctune*tation, IRB
ientr on this shrdy, each site willglgta{lg Og&:
cl:...:iE!i::iag!-s-:ilailli'-!:il.i-{-! 
c,r'ii:sl:l f'-'l r:rl: i':'-'r*r*r ru.r:'r u'\ L'|rr ^,,- ".' '"--
ffiatmgttrstthtltott,s..*'*stbereviervedandapprovedbi'tlreoHRS
If a patient is registered on-sfirdy but does uot receive any protocol therapy, baselile data will be collected
ald submitted according to Data Collection (Sectiou 6.1) and Records to be Kept (Section l3)- No firther
fullow-up data will be clo[ected. The re*$o$ for not starting protocol therapy will be doclunented-
6. $tuily Pararneters
The following tes6 ard evaluations will be pertbrured according to the schedule below- Baseline (i.e., pre-
study) evahations nlnt be performed ao loiger than 30 days{+l- 3 duy*} prior to t}rerapy, unless otherwise
indicated in one of the foohotes below the table. For nll cycles rubsequent to rycle l, th*re is a window of
+/- I days allowed for completion of all protocol evaluations, Delays due ta holid*ys, weekends, or inclement
weather will not be cousidered deviatious.
approved cousent form).
-t9-

Tirle: A phnse 2 trial of liposoual doxsrubicin and mrbuplatin in patients with E& PR, HER2 negntive breast cancer (TNBC)
IEI
f,vrluations
Pr*-Study
1{*ekl"v
Fr:icr fa E*ch
Cyetcd
End of
Trentrnenf9
Otber
Si grred hfonnetl conseut
x
Inilinl Histort & Phy:ical
x
Lrtcrim Histoay & Physical with Vitnl
Sips
x
x
Toxicity Assessnteut
xil
xr{
x
ECOG Perfonnance Skhts
x
x
x
Weieht and Heieht
x
x
CBC. differential. plateletsr
xl
\al
xt
X
Senun Clrenristriesz
X1
xl
X
Urinalvsis. l4horu creatinine clearance
x
Liver Enzymesl
YI
vl
x
EKG
x
IdLlGA ScanT
x
X7
)s
Borre scan, CT CAP with conhast
xr)
Xt:
xr!
Senun or Urire Pregnancy Test{
x
Turrror rneasnrernenlsJ
x
x
x
Recrurertteto
xl0
xl0
Sun'ival lt
x
fulamnrosram and,'or US. or MRIIJ
x
xlt
BrEast hrnror tissuel6
X
xl6
Fresh hrnor tirsue for PDXi?
xr7
\Vhole blood collection for researctr
xl8
Oualitv of life sruvev instruruents
x
xle
x
xre
Trunor genouric ttstiug
x
x20
x)0
lt"rt piiir.nrt" for blood2I
xlr
x21
Lrununohistochemiutry for ER. PR and
FISH for HER2
X?3
iitaaPY to reconfirm eligibilitY
if tlrere appea1^5, to be arry deterioration in the parierrt'r $tafus duing the ioten'al btt*'een regisfiation a$d treaturetrt. Baseline
ruinalysis L16; 24 hour urine creatinine for detenuirutioo of cestirine clearatce will be done only prior to first cycle. If either
SGOToT SGpT are 1.5-2.5XtheULN, ahepatitis pauelwill b€ perfonned. CBC to be doueweekly only duringweekly.faclitaxll
and prior to each cycle of liposornal dosrnrbicin and carboplxin (and prior to each Dogetaxel or Ab'raxaae if rtceil'ing this in
place of paclitaxel &re to prel'iour tosicity).
Z. Includes:blecrolyes 6sodiru* pot*seiu* chloride" car$on dioxide. calciuu), BIIN, sEnm creatinim- glucose,
3. Lrcludes: Total bilirutrin, scdifscfrf. akaline phosphatase, albuniu. total protein. If either SGOT or SGPT are 1.5'2.5X the
ULN. a hepatitis panel will be perforued.
4, Wouren of chilAhariug pot€$tifu must hsve a negative pre€slarcy rest r.erified by senrm or trine BHCG rvithin I week prior to
elrollment.
i. Diseasr nreasgrable by physic*l e.xarnination per{ormed at baseline rvill be re-el'altraled aftEr each cycle oftheiapy u*ing calipers'
Surgical specimar is to 51ive size of residual tuuror.
6. rvithb ?3 logrs of tlre stix of rhE rycle beyond Cycle l. Cycles are defined $$ .very 38 days (+l- 3 rdays) far both pre' and post-
surgical iherapies. Detays due to tralidays, weekeuds. or holidays will nst be considerd a deviation'.
T. Ferfsrmed at bauelinc, within 30 days prior to first dose and within one moulh after cycle 4 dore of liposorual doxorubicur or
epinrbicin. carboptaiin (see $ection 7.i.l.l). The latler evaluation mu*t be completed prior to surgery' Echocardiograur rnay be
used if MUGA six11 is 11ot ao*ailable, but the ssrw tesl must be used tluoug&out the snrdy to er"altrate LVEF.
g. For patiants experiencing toxicity. corurts will be repeated as outlined iu Seclion ?.4 for iudividual toKicify sssessulerts.
9. Conrpleted I mouth aft:er the tast dose of liposornal doxorubicin or epinrbicin (see footrote ?). cartoplatin, paclit*xel (or
docetaxel or abraxane) tre#tne$t.
10. patieuts ntill be followed for rscurrence every 6 mouths. Tinre to recrure&ce will be follo$'ed using inragi[g scurs/trunor
evaluation for s;rnptou evaluatiou to Aocume$i first docrunentation of r*lapse. Biopsy wilt be perfornred t'o docurue0t relapse '
-7fi -

I L patiants r*"ill be fo[owed for srurivat every 6 morrths for tlre first 3 yeart than annually therenfier' A telephone call uraybs made
for nrr.ir.al f"ru**p.-s*"ivnl will be rnonitored fcrup to 20 yeans,fotlo*'ing cornpletia[ of chenrother*py'
12. Imaging by u*ururogra$ andlsr utuaso,*d;;; rr* p.rro""i widris 6 t*ott * of study eutrv and/or breast MRI imaEng
$,ithio 30 days of srudy entry. pET-CT is rllowed as an xlternatire sraging st$dy to qT ql a*d tl'hole bo& bone scan if
deerned ap,propriate by treaii[g physieian. Additioual inraging *fte*.y"L tiiU U*-t""*a on clinical suspicion and worknp for
met*$tatic diseese'
t3. fte first 6 paiients will need ts b€ &ssEssEd far toxicity yia telephone weekly for Cycle. I only'
14. perfomred wheu &e pati€11r cornes io for t[eir visit. Tlie toricity evslturion is optional in bewean I'isitr *nd at the discretion of
the Inveiligator. If a; asressnrer( is dorre. it uray be done or,er tire phoue. Long ierur toxiciry will be monltored during foltrun'up
for sru'l'ivsl.
15. Imaging with *r**rnrography arr#or.ultrasorurd- or breast i{RI is to be perfonned prior to fu'st cycle. '{dditional iprasing to be
pedomled as clinically indicated.
16. Alt patients u,ill be required to undergo $ nes/ &$nor biopsy prior to inifiation of chemotherapy. If the diagrrosis of triple
negstil.e brcart cancer was msdr on FNA. c*rr$mration of rxole*ular statffi FR-/pR-/'Htmtly **u biopry is required prior
to study i*itintion rf patient has a core lriopry doue-prior tothe lsegcn uio}sy thatccnfinrx TbrBC' th€ry do mt nEed to v!'ait
for the rEsearch biopsy result. FFPE tinsue'is to * sent for pathology *o*"tt with tke. breast pafiologist at Rltr/JUH' for
genomic analysis by Fogndation Medicine, *na i* IHC by the xistopathologry and Imaq,rne $ore at cINJ' For qtrchrononr
disease, biopsy sf eaeh focu$ will be done aud erch focus wlfl also be sent for testitg with Foufidlrtion Medici$e or other similar
tumor genonric prafiling platfonn.
l?. Fresh tissue will beobtained at tirue of deJinitive breast surgery ou idqrtification of gross rusidusl disease' Tissue xill t'e
presened as Per SOP.
Ig. Two prple top *n* gOfg ttrbe* l$,il] be rollected at study ertry, se$t 1o the Bioopeciureo Repasitory Service, ald stored for
future studies.
1g. (frulity of life sunrey instnrnrmts (F,{CT-B, Appe0dix c; Pittsbyr{-sleerr Quatity Index- Appen'dix D: A distrEss Assesses$nent'
Appandix & Hearth Hope hrdex Appendix frlr* optio"*t arra Jin ue coipletetl *t baseline Srior to any chemotherapy)' after
cyele 4 liposornal doxo*ti"irrl.urtojtotirt *d *0.r'dor" 12 paclitaxel. Hearth Hope Index (Appendix F) will also be done at the
star.t of adjtrvanl paclitaxel. A Distress Arse*sment (Appendix E. equivalent at siies acceptable) will be adnrinistered ftriveu by
the nredical healta teclurician) and ccores rvill t " "rrto.a 
hto {re rrreclical record. social work will be notified of score resulls as
par clinical protocols set fo*h by NCCN guidelines'
20. fFpE tissue to be seut to Forurdatiou hledicine or for use $iith ofhe,r arnilable genonric plat$or:rx for gelomrc testing pretreahnant
and/or after ,*g*o/ if sr,,r*, residual disease idmtifted, lnitiatin[ of teatrient is not contingent up'o'$ obt*ining resul*' It is
recon$rended, but not rnandatory, th*t s"*o*i. testirg be priormed at tinle of recurrence. P*timts nray opt againrt *'ending for
Found*riongne cDN testing rrhich ruay 1""* "ri.f&*Jt 
cost and is ordered lry ihe treating physician" but uot research only
genomic tesling r.hich is at no cosl to tlle patielt and is ordered by the study PL
il. op{io,al at time p*int; veniprurcture for l0 nr} of blood will be drarvn (h cen-r'ree DNA BCT $lreck l08rl blood collection htbe
for stabilizstio, of cel!&ee plarma DNA; at rriaprosis. at cycle 4 liposomal do..corubicin' afld at 6 mondr interrals for total of 3
yeus tlren arurualty to complete 5 years rrnrers recture'ce oscl$s sooner (nt which time collestior is disco*ti'ued)' Plasma will
G prep*red and cryopreserl.ed at -io'C lbr firtue analysis with trunor genornic profilinS'
22. At the tiure ora"n*rii'u ,*gery, irmruuohistochulistry for estrogen re..p,* (sR) an{ Pro8resteront rtce[]tor (PR)' afld IISH for
HER2 will be ordered on aii ,poi*"* with grors re*iiual disease at thrdiscretion of thc trcating physicia[ ot sh,*y pL
6.1 Required D*te Collsction
Required infonuation for each patient rvill include the following: Patieut characteristics/demogg*phics, breast
caucer pathologic ard molecular feattues, AJCC TNM stagJ (cfinical at diapurosis" pathologic at time of
defi,itive srugery)" Study heahneut adruinistered. Other trea.-trueut includiug radiation therapy, s[rgery. and
other medical theiapies, Adr*r*" event$ as clescribed in section 7" Breast callcer events (local, regional, and
distant recuneucs$i Second primsry caocer eveots including second priuraly breast caucer, Sruvival'
6.2 Pathology strd Correlstivr $tudie*
Up to six ctnes will be obtsircd druing Se gy-treltment reseffch biopsy. oue core will be sent to R$/JUH
pathology to pr.pare a furmalin-n*.ai*iomo-embedded,(r'rPE) tissue-block and then to uudergo standard
histologic review antl molecular a*alysis (including ER, PR, rrERz *ualysis)- FFPE tumor tissue from the
-21 -
5ffiorrrbicirrarrdc*r.boplatinirrpatientswittrER.PR.HER2negfitivebresstcallcer(TNBC}

Tirle: A phnse 2 trial of liposoual doxorubiciu and c*rboplatin in patieuts with ER* PR- HEpl negative breast cancer (TNBC)
I-I
pathologry $peeimer will be sent fol testing by Formdation Medicin* fur geuoruic profiling. Ttre requisition
'fo, genomic testing lvill be prepared by rhi Biospecimen Repository Serviee (BRS). The remaining five will
6e sent to BRS. fnS dtt-ge,lrerate FFPE on tlrese pre-treaturenf cores with 2-3 cores per cassefte- For
inaderyute biopsy ti*sue, addiilounl biopsier uay be perfonned aud FFPE seut for genomic analysir. For
patients with gross residtial disease (GRD) at tirne of definitive srugery, defined 65 :,Jmnt, t[nror tissrre rvill
iie sent for pithologic aualysis (including histology and if indicated. analysis for ER, PR. and HER?).
Correlative shrd^ies tiitt t * plrfonneO txr tnruor specimerx obtained &uing the study: geno[ric profiling and
IHC ou pre-koatruent biopsies aud on GRD" For GRD >lcm in size, patient'derived xeuogralls (PDX) will
be creatid as described below- Recurrent disease will be biopsied for cotfirmation (where clinically
appropriate) and tlrose speciureus Brith adequate tissue rvill be seut for genomic analysis to detemrine
developmeut of serial somntic mutatious. nbod specimens will be obfained at tiured iutervals in Streck cell-
free DNA BCT hrbes ancl seut to the Biospeciruen Repository far the isolation of plasr:ra as follows:
Velipunctrue for l0 url of blood will be dlawn (in Celt-Free DN.A, BCT Stleck l0url blood collection tube
tbr stabilizatiou of cell-free plasma DNA) at diagnosis, at cycle 4 liposornal doxorubicin, aud at 6 month
iutervals for total of 3 years ther annually to conrpGte 5 years unless reflxlrence oceurs sootrer (at which point
collectiou is stopped). Blood tube can be kept at-room ternperatue until processed but ntust be irnrnediately
rnixed by geutle inversio$ I to l0 times" po XOf sfore in reliigerator or Seezer. For separation, centriflrge
whole Uiooa at 300 x g for Z0 rrinutes at rooru tempemtue. Remove fhe upper plas[ra layer and tansfer to a
uew conical tube. Celtr-ifuge tlre plasma at 5000 x I for 10 uinutes. Plasma should be cryopresert'ed at -80"C
for frture to isolation of eell-free DNA for analysis with hruror genouric profiling.
6.I Mutstion*l Aualysisl$enamic Proliliug by Trrgeted Next Generttion Stquencing
A tuuor sarrple is required; a trxuor blo*k i* *tro*gly prefered. Tumor blocks rvill be suburitted to Fouudafion
Medicine or au altenrative conuuercial laboratorv for genomic profiling. Where adequate tissue re$mins'
hpuor tissue will be requested for immtrrohistochemical staining" If the pathqlogy departmeut ytll not apee
to submit a bloek that can be kept for research pruloses, the block slrould be submitted arrd Biospeciruen
Repository Serviee (BRS) will procure samples of the truuor and relur:r lhe block to the pathologry deparfment
that subtrdtted it.
Formaliu-fixed, paraffiu embedded (ffPE) hrmor ofprc-treatment and gtoss residual disease uray be eent to
Forurdatiol M#cine (Cambridge, lt*n) for targeted sequeucing as ordered by the freating physician i$ the
EMR. Otler CllA-ce*fied conunerciat paugenoruic testing plotfonrx rnay be used alternatively but ordered
by the shrdy pI. The Cl,I.A-certified Forxrdation0ne platfonu utilizes cliuical grade nexf-generahon
sequepcing (NcS) to identiff genomic alterntious finutntious, copy utuuber alterations, insertions. deletio0s.
,"*g*ieuts) in roup&ly ili "uo"*r-r*lated 
geues. Foturdation Ivfedicine rvill perfonn DNA hybridizatiou.
Iibrary ionstruction, hi;br.id capttue. and thel sequeneing using the Ilhuuina HiSeq 2000 (depth of coverage
500)Gl000X). h cases where serial tuuror speciruens are available, e"g. serial biopsy at tirue of progression
or recu,,"oce, that hruror tissue will also be sequenced to ideutif,i additioual mutations that deveiop. The
mutational spectnrm and nrunber of mutctions observed will be described as a fiurctioa of patient aud tuinor
cSaracteristics. Second*ry exploratory analysis will be to determine association with prcsence of specific geue
glrtatiol#pathway utter*tlonr with patholog.ic complete response (pCR), reclurence free stuvival (RFs)' and
overall suvival (tis). wtrote blood ivill be coltected for isolatiou of gerroruic DNA. If caucer genes associated
with faurilial predisposition ale fourd in hunor samples raisiug the possibilif.v $ a ger:}li[e mutatiou. a
reconrmeudation for assessment by a genetie couuseloi in the Hereditary oncolopy Pfeve rtion and Evaluatrou
pIopamottl,*rrlefuritir,e.gertetic..testirrgwouldh*iI""n{:::
Moleeulal Trundf
'go genoxric proiiliug, ttre Honest Broker will be

Tirle: A phase 2 trial of liposounl doxorubicin and carboplatin in patients with ER. PR HER2 $egative breast cartcer (TNBC)
I-I
co[tectedtore1rospeetivelyemollpatientsigrlreFrecisionMedicineProfocolf.barrirrgshrdy
closure) ond penrling pati*nt consent.
6"{ Correl*tiv* $trldies
All specirnens witt be collected throug& the Biospeeimgu Repository Service in accordauce with Honest
Broker procedures-to protect patieat lAiutity. ffPt blocks will be $ent to Forurdation Medicine or used in
other couunercial Cli,q-certified u*qrr*rr"irrg platfonns for talgeted sequeucin8. Genomic results will be
reviewed at the weekly Molecular Truuor goard where all identifiers *re removed to prcserve patieut privacy-
Where tissue is avnilable, iprmrurohistocheruistry (IHC) an#or FISH sttrdies ilray be med to confurr
aarplificatiols or h.anslocations and detenuine the association befween genomic alteration$ and altered protein
expressiou, e.g. mes$ure corcsrdau*E belween p53 IHC with p53 urutation rype, me&flre pAKT a$d pERK
in tumors with receptor tyrosine kinase 1RfK) mutstiorls as downstreaur effectors indicating activotion of that
patlway. This will du*rrrt*t tbat downstream targets nray be au imporlant therapeutic focus whea specific
RTK m*tationg are obsexed. IHC will tre perfonned in tlre Aistopathology and huaging Core. For exploratorY
analysis, we will also evaluate and aualyze rcutine H&E slides of tissue for presence of tuuror infittrxtittg
iv"riuo.ivt.s which will be correlatet{ rviih patient outconres. Although TNBC and HER2+ subtypes have the
rrigfi*rt levels of hulor infilhating lSurplrocytes (TILS) and a higlrer percentaeie of fiLs has been associated
*iiu irrrproued mrvivel to both *i.iri"*it ani neoadjuvatt therapy with anthracyclhes [78-80i, why varying
levels of nl* are obseffed remsin* to be elucidaied. Therefore, we will evaluate pre- nnd post-treatment
GRD for TILs. Usiug routifie H&E section$, oru' pathologist will evaluate each specimeu for preserce of
sfronral TILs in a blinded fashion and score for percentags of stlotna containing lymphocyfes [80,81]' We
will use TILs s$ a binary valiable (defirred by otlrer:s as <500./o or >50Yo) and corelate' iil ar exploratory
analysis, with pCR rate and other clinical oufcomes. We will also assess presence of TILs fbr associatio[s
withspeetrun of geuomic alteratiou* and with mutational burden.
6.5 Plfient-Derived Xenogrrfts antl Ex trruo Arslys
6.5.1 PDXRrtionds
Gross residual disease (cRD) iu TNBC afterueoatljuvant chemotherapy predicts for risk ofrelapse. Equally
iurportagt to identifying **f.rs that predict for oRD with the DoxcAR then wP neondjuvant regiuren,
rvo*ld be to be aUle to identify potentially effective therapies that coulrt be used at tirne of relapse' It is
hypothesizecl tSat the mutationai landscafe of a breast ttuuor may: a) be represetrtative of thst forutd at
relapse; b) predict far response to subsequent c$otoxic or targeted therapies. Patient-derived xenoggafls
pUX: wiil be utilized to validate therapetrtic ,**ponu"c where each PDX will reflect *u individtr*l patieut's
TNBC. By utiliziug this model, tbe mCI$t effective therapy will be identified a priori for a speclfic geuoulic
profile 
"o,1**poodilg 
$o aa1,specific patient. Iu additiou" it will be used to identi$ who is likely to relapse
afier treatmeut *iir, b".ritaxei *nd *trl*t huuors would demonskate resistauce to cyclophosphamide as
proof of prilrciple.
6.5.2 Design
T*ble l. Proposeil l3*lrs fur PDX aad rx tivo as*ys
T{rstt
Agcilt
P53
Weel orCHK1 inhibitors
PIK3CA
PlSfinh. or dual P|3K*mTOR inh.
NOTCHl
Gamma secretase inh.
FGF/FGFR
FGFR inh.
Cytotcrlns
PBclitroxel
er bulin
cTx
vinorelbine
tapecitntine
-71 -
At fhe time of slugsry, pafients with GRD will lrave fumor
sectioned for: a) pathology for clinical analysis, b) IHC, a$d c)
fiesh tissue (0.05c[r iu one diurensio[) preserued iI} fresh RPMI

Tirle: A l$6$2,tnd_AftbSgeggal doxonrbicin and cartroplatin fur paliemts with E& pR- HER2 tregative breasl cancer (I!'{BC}
INI
Upon receipt by the research laboratory, ooe sarall portiou of the tissue (0.05 cm in one dimenriot) will be
placed irrto neuhal buffered fonrralin solution for lristology. TIre remaining portion of the tissue will be cut
into near eqrral pieces for irnplantarion into PDX model mice. The number of rrice will be de,tennined by
the size of the tirsue prsvided. CINJ hss $uccessfidly established PDX modelr of TNBC with less than 3
passeges. PDX will be ueated in NODISCID mice as a hrmor cell ineilbator for each individual patient with
GRD similar to other prrblished protocols [8?J. Tr,nnot cells, oumber based or hril]or weight, will be
orthotopically iqiected iuto the $rouse nmmmary fat pad (P0 generation), lrarvested at appropriate tmnor
size, and cells cryopreserved es a source for all subsequent experiments. Once prepared, PDX specimen will
be deidentilied and packaged according to OF{SA packing requirements and shipped to the lab ofDr. Celeste
Nelsou iu the departmeut of Chemical arrd Biological Engineering at Plincetou University.
AtI, 
explant (ex viru) crrlhre of cells will also be pgown on the surface of biologically
ineffincercelIdissociatiorr.keepiugstrorna1tissttesintact'Dnrgrespoffieassays
(Response3DX sr simitar *ssoy) will be performed on explauts" PDX will be &ozer viable by and fexted in
Response3DXIH or sirnilardrug screenirrg platforms. Molecular char:acterization of samples from primary
tumor rnaterial as compflled to established PDX will provide valuable infarmation on the predictive
relevance of these models aud ou'approach" A porlion ofthe PDX tissue will be retained for custom analysis
and characterization of the PDX nrodel as well as geueratiou of prinrnry cell lines for in vitro drug testing.
A portion of tumor aud cryopreserved cells will be retru:red tbr sequencing and additional laboratory-bared
evaluation. Histology and IHC will be perfonued prior to pharmacolog,y. .E,{ vruo pharmacology will be
performed rrsing either the first passalre or if su{ficient nruuber of cells, $ot!-propaliated c,ells" Treahnent of
secoud generatiou nlouse avatars with trmors will occur in parallel or subsequent to ex vivo assays. Ex vivo
data may be used to gnride drug selectiou. Shrdies to be perfomred ou turnors inchrde markert of apnptosis,
prolifrration, urorphology. Preliminary data coutfiru that patient-specific histology, ttuuor architectrue.
moleculal feahu'es, biornnrkers are uraintained over passage.
Dnrg response tests rvill proceed by: 1) in viva testing of PDX in nrice; 2) ex I'fvo pharmacologic assays. A
nrirduluru of 50,000 viable huuor cells from Pl or P2 (second or third passage in rnice respectively) will be
injected iuto l-6 NOD/SCID ruice (mnnber to be based on total cells available), ard Srswll until tru:rors
reach an average size of 200uun3. Groups of 60 mice will be raudourized to {brr treahtrent ann*: l) vehicle
eouhol, 2) targeted ageut, 3) cytotoxin (eribulin, capecitabine. qr vinotelbirre), 4) cyfotoxin and targeted
agent (see Table I for exarnples of ageuts). It should be nofed thal 80 mice are typically inoculated to eustue
60 truuors with grorvth to the proper size. Dnrg-specific dosing over *6-8 rveeks will be based orr estatrlished
methods, with uronitortag ibr body weiglrt, tumor size. and clilical observations. At termination, trunor
(where ar.ailable) will be rcsected. measrued, aud FFPE made and hunor specimens stored for futwe
molecularlgenomic sftrd.ies and resequencing. PDX hunors will also be evaluatetl for morphology, Ki67,
p53, opoptotic rnarkers, and phosphorylated proteius in relevaat targeted pathways. .E"r I'rvo Response3DX
or sigrilnr drug assays wilt be per{brued on cells }om first pas$oge or rou-propagated cells, at multiple
concerfiatioor to deiennine IC5q for auy giveu tuuror. Cells will be treated with various cytotoxins, targeted
agents or combinatious. Results fiom ar urvo assays ruay help direct treatment of PDX. Exact targeted ageots
ou,l cytotoxius will be detennirred by genornic results. Histology and IHC will be perfonued prior to
phalmacology.
As prnof of concept for respouse to CTX nnd WP, each PDX will be treated with either agent, validate the
relatiouship between ALDHI expression and reduced sensitivity to CTX, aud deter:nine the predictive value
in knowing rvhich patients harbor trunors fhat rnay prcgress or relapse after WP due to intriusic resi$ta$ce.
-24 -

Title:A
doxonrbicin and c*rlmplatirr in patiants witlr E& pR- HER2 nBgative breasl cancer (T}{BC}
NGS results &om resistmt PDX will be compared to genomic profile in fumors &am patients returdng after
WP" We rvould expect that PDX showiug no reduction in fimror volume will correspond to truuors in pntients
for whom tlrcre will be a higher risk for futrue relapse or progression of disease dtuing treahnent with lSP.
Dnrg selection fior testing in pDX and r* rivo assays will be guided by each tusor's genomic alterations.
Given tlre mutational fiequencies observed iu prelirninary seqllencing, we anticipate identification of p53,
PIK3CA, NOTCHI, aud FGF patlrway alteralions. Targeted ageut* are de{ined in Table I " We will purclrase
clinical gade dnrgs from licensed supplierr of phanuacerrtical coulp*rly products aud/or our research
plrarmacy, trut we will also approach phnrma to obmin approval to obtain cliuical grade dnrg directly fiom
the mnnufactruer. Cytotoxins will be purchased or obtained t'om orr rcsearcb phnrmacy as available. For
cytotoxin testing alone and in eorubination with targeted agent, we will prioritize drug selection from the
right calunn as they appear in Table l. Cyclophosphandde and paclitaxel will not be used lbr combinatorial
testing. Results &our PDX and eJ vlr.u assays will not be used to direct teatrnent decisious for patietts.
7" Treatment Phn
7.1 General Con*iderstious
A cycle is defined as au intervel of 38 days for DOIUCAR and ax a weekly interval for WP (delays due to
holidays, weekends and inclement weather will be penuitted aud will sot tre corurted as a protocol violation).
No investigationnl or commercial ageats or therapies otber than those described lxlow may be administered
with the iutent to Ueat the patient's nraliguaucy rvith this exception: peg-frlgrastinr can be giveu for the
treafiuent of neuhopenia, at the discretion of the treating physiciau. drrilg feahnent with liposorual
doxorubicin and carboplatirr. Shrdy treatmert rvill be adrninistered unfil disease recun'eoce or proStression,
2ud primary maligpancy {except cruatively hented nouurelflnoma skin caucer or carcinomn ia situ of the
cervix). unacceptable toxicity or withdrawal of cotsent occurs. Patieuts may di*continue therapy at auy time
for any reason.
Schedule of Therapl'
Neondjuvant
DO)iUC.dlt
Drug
Dose
Doring inten'rl
Phnned ilur*tlon
Liposornal
doxonrbicin t!OX)
3&up"ur2 I! or"er 90 minutes
for first infurion then 60
rninutes subseqrieutly
Day I
evc.r1 4 n"eeks
eycles 1*4 (one cycle :4
*'eekr)
Carboplatin (CAR)
AUC 5 trV over 30 - 60
minutcs
D*y I
every 4 we*ke
cyder 14 (oue cycle = 4
weeks)
Drllnitlve br"enst surget)*
Adjuvrut 11P
Dt'trge'b'c
Do*e
Dosins intelr'*l
Plenned duration
\IrP
80 mgfnrl IV alier 60
minutssl
I#erkly {one
cycle = 4 u'eeks)
12 doser
a*follox'slreforeeachpaclitaxeldose:dexamethasonet0rrrgiv,fanro,tidine2&rrg.
diphe,nhydranrine ?Smg, An equivalent dose of oth€r'steroid nray be substihlred for dermmethasone. Alternatiue IV H2 blocker
may be giveu; cirn*idine 300 mg. r*nitidine 50 mS.
b Central vefious access is al the intertigatot's discretiou.
t Patients will be enrolled io receive the follorning trealrrert: 4 cycles of oeoadjur.ant carboplatin and liposoural doxcnrbicin
a&ninistered every 28 dayc (ca&oplath AUC 5. liposorual doxonrbicin S0urpdmr) fotlowed by delinitive breast strgery aod tlren
12 weeks of weetly paclitaxel (80 mg/tr2). In the event that the patient has a reaction to paclitaxel, tlre patient nuy be treated
with docetaxel or abraxale st staudard dosiry paxa$reters at the treatnrent physici*n's discretion. Definitive breast surgery will
-25

be petdouned no sooner than foru weeks fiour tlre last dose of liposornal do,xorubicir. Patients q'ill slso recEive *dditional therapy,
e .g. 6djrw'*rt rndiation therryy, *r clinic*lly indicatEd al tlu treatirrg physician',* discretion,
?.1.1 Drug Sptcilic Safety [Ionitoring Procetlures
I{ote: When t}rere is a shortage of cloxil at the
, patients will be
iive autluacycline.
Treahrrent would theu corxist of epinrbicin (60 mSI#), carboplatirr (AUC 5) in patients with ER, PgR.
HER! negetivo brEast co$cer"
Epinrbiciu and c.srbcplath witl be given on Day I of a 28 day cycle. Epirubicin will be celculated trsing
the patient's actual rrreight in the determiuetion of body $$face area. fV administration will be given over
15 to ?0 miautes.
1g tbe evert that a patient lm* s reection to paclitaxel, tbey will be allowed to $witch to either docetaxel or
abrnxarc pnr iuxtitrtionnl guidelines *t the heating physician's dixeretion. Additionally, if a patient has a
reaction m Aoxl aud the ueatiug p$ysician believes it is in the pntient'e best interest to &eat the patieut
with epirubicin irste.sd, this may be allowed. However" tlrc physician rnust first consult with the PI for
approval"
All teahnent parameters, safety paranreler$ and requirements will be followed as per protocol and outlined
in tlrc followin$ sections.
7.1.t Cmdi*c $*frty Monitoring
Crrdiac Srfetv Monitorins
@tiou&*ctiou(L1,:EF)detenninatioagwil1beperformedona1lpatientspriorto
enrollment in the trial- Pntients will uot be enrolled if L\IEF'is below institutioaal oorr*al limits-
Ouce oo $fudy, all pafieuts will be nronitored for a decrease in left veutricular ejection &action (LlEf) based
on the criterie below"
Trga6entwith liposomal doxonrbicin or epinfticiu shouldbe discontioued if there is cardiac dysfirnction as
indic*ted by:
r symptouratic arrhythmia or co$ge$tive heart failrre, or
r a decrease in LVEF to below tlre institrrtional lower limit of uonnal gnd at least an absolute 5 percertage
pohts decrease *orll the p*tieut's baselfule LYEF valtre (e.g., 45Yo to 400.6), or
1 trrry sbsolute decre"$se of 15 porcentage point* or $Isre Sour {he patie*t's bsseline value (e.g- 609o to
4see).
-?6 -
Tirle: A phnse 3 trial of tiposomal doxorubicin and ca*uplatin in p*tit*ts with E& p& HERS negxtive brea$t cancer (TNBC)
I-I
allowed to receive treaturc$t with epirubicinl

Tirle: A Ph*se ? tial of liposornal &-lorubicin and carboplatin in patients with EIt" PR" HER2 negative breast cancer (TNBC)
INI
MUG"{ or ICHO (I,YEF] Schedule for sll patients:
r kjor anthracycliue doses exceedfug 360 mBlm2 for doxonrbiciu (fircluding liposornnl doxonrbicini or
720 rng/m? for epinrbicin *re not allowed.
LYEF assessntert perfonued by MUGA scan prior to cycle I arrd after cycle 4 of liposornal doxonrbicin or
epinrbicin and earboplatin lreatmeut. The latter evaluation nrust be courpleted prior to surgery"
Echocardiogmm may be rxed if MUGA scau is not available. but tlre same test mrwt be used throug$out fhe
shrdy to evaluate LVEF.
7.2 Doss Cf,lcr*stion
Doses of liposonul doxanfiicin or: epinrbicin will be calculated using the patient's actual weig&t in the
determination nf body surface area. A variance af So/a of the calculated tofal dose will be allowed.
BSA (m2) :
Doses of carboplatiu will be caleulated based on senrm creatinine using the nrodilied Calvert fonnula:
Total dose (rng) = Target AUC (mpfml, x nrin) x [Crcafinine Cleararrce (ml/urin) + 25]
Creatinine clearance can either be nreasured or estimnted using the Coclcroft-Cault fonnula, as follows:
Creatinine Clearance furlJmfur} = (140 - age inygn$) x (wei$ht in kg} x 0.85
72 x serum creatinine $nf/dl")
7.3 Trr*tmsrt .A,*ministration
Carboplafin (AUC 5) and either liposoural doxorubicin 30 m$urr or epinrbicin 60 mdm? will be
administered ou Day I of each 28-day cycle. Affer defrnitive srugery, paclitaxel 80 rnglm2 IV will be
administered ou Day I of each week for total 12 doses.
Generul inshrctions:
r The CTCAE v4.0 must be used to grada the severity of adverse evEuts {AE$.
r All doses must be based ou the AE requiriug the greate*t modification.
e Chemotherapy doses that have beea redrrced nray uot be escalated.
e Chemofherapy should be lreld for at least I week rultil arry AE requiring dose rnodificafion returrls to S
grade I unless indicated otherwise in the freatmeul firanftgement sectious/tables. lf recovery to < grade I
(or to other level specified) has uol cccurred a{ter 3 weeks of delay, chemotherspy must be discoutinued.
r In the eveat of hrmor recurreuee, chemotherapy should be discot$imred. Fruther therapy is at the
investigntor's discretion.
e Antiemetic therapy should be administered accsrding to Nstional Cornprcheusive Cancer Network
NCCI.I) or Amerjc.an Society of Clinical Oucology (ASCO) clirical practice guidelines.
r Management of aaemia -Chemotherapy should nol proceed with > gr*de 3 aneuda. Transfirsion is
acceptable for iarproving the hemoglobin value to allorv therapy to continue without delay. The patient
shonld be assessed to nrle out other cau$es of anemia. Use of erttthrapaiesis-stimulating qgarls is
prohibited.
iaigltr(cn)nwrgnr(fu)
-r"t -

doxorubicin urd ra*oplatin in patieirts with EB* pR. HER2 negative breast cancer (TNBC)
I
?3.f C*rboplrtiu
C*$oplatin at target AUC : 5 mglnlJmin will be administered by IV iufusiol over 30 * 60
miuutes.
1.3,2 Lipotomd lloxorubicin
To minirnire the risk of infixion-related re*ctions. the Iirst iafusion of liporomal doxorsbicin should
be administered over 90 miuute*.
If no infrrsion-related resctions are noted wirh the initial infirsion, subsequeut infirsiors will ocer$ over
60 minutes.
73'5 ffffiffi of a shortagr ofdoxiulipasomsl dCIxorubicin at &e Rutgers caucer Insritute ofNew Jersey.
patientu will be s11oured to receive epirnbicin. Epirubiciuwill Irc given by fv adrrrinistratiCIn over 15
to 20 misutes.
1"3.4 Psclitrxel
Paclitaxel wiu be giveu by I!'administration over 60 minutes.
7.3.5 Docetrxel
In tlre event the patient has a reaction to paclitaxel, they will be allowed to switch to either docetaxel
or abr5;1ere. Docetaxel will be grven byIV adrniuistation over 60 minutes per kstitutional
guidelines.
7.3.6 Abraxsne
In the event the patient has a reactiou to paclitaxel, they will be {loryd to switch to either docetaxel
or abrax*!r*. *U***r will be given by IV adrninistration gver 30 minutes per Institution*l
guidelines.
7.3.7 Additiarrl ThcrnPY
Breast sluge,ry, mastectomy or breast conserving $urgety! will be at.the discretioo of the tr:eating
physician. Houiever, all procedures require lyrup[i node evaluatiou with ruinimuu of sentinel lytnph
naie biopsy. Choice of radiation tberapy, treahueut fields, and keahuent sclredule will be at tlre
discretiou of tl* treating radiation oo*oiogi*t. Whote breast radiation should begin within 6 weeks
following the l*st dase if chemoth*rapy. ilegional nodal basin irradiation is at the discretion of the
trerting r*diation oncologist. psrtial url**t ii*diuti"o is not pemritted. Post-mastectomy radiation
ttrerap| is et the disc*etidn of the treating radiation oncologist. Therapy for progressive disease or
resurent disease is st fhe discretion of the *eatiug rnedical oncologist. However, the Moleculal Tmnor
Bonrd may provide recornnrendations for ther*py based ou the genomic profile tbr that patieut's huuor'
?.{ Dore Modiliestiuns
Chemothernpy dose $riu be adjusted according to fte system showing the greatest degpee of toxicity'
Toxicifie*/rdverse eveuts will be gpaded *iry es NCI Comuron Toudnology criteria for Adverse Eveots,
ver$ion 4.0. patients are *llowed a maxim[m of 2 dose reductioas. If toxicity or adverse everts car$e orle
st'dy ar*g to Ue treH, all sildy dnrg doses will be held until criteria is ret to resurne dosiug' chemotherapy
-?8-

Tirle: A Fhase 2 trial of lipororual doxombicin aud mrbaptatin in ptients with E& pR" HER.2 negative breast cancer (JNBC)
INI
will be he,trd for e ulaximum of 3 weeks for toxicify o{ fldverse events. If after 3 weekB no rece$ery is seeu'
study dnrgr will be pennaneutty dineontinued ard ttre patieirf will be rsmoved &om ths rtudy.
Tre*tment with D0)CIL/lipo$omnl doxonrbicin or epirubicin should be discoutinued if tlrere is cudinc
dysfirnction as indicated by:
. symptmratic arrhytluuia or corse$tive hear:t faihue' or
r a decrease ia LVEF to below tke institutiooal lower limit of nonual and at le*st an absolute 5 percentage
points decrea*e &our the p*tient"s haselise LYEF value (e.g., 459ln to 4090), or
. a$y absolute decrease of l5 perceutage points or more fiour the patieut's baseliue value (e.g. 60Yo to 45W-
Treatrnent with epinrbicin is sllowed if Doxlllliposoural doxorubicin ruust be discontinued due to toxicity
at tlre treating physician'e discretiion.
Dose rcduction is planned i1 case of severe hemntologiqal nnd/or non-he,mctologicrl toxicities as follows:
Carboplatin: &omAUC 5 mg/xnumin to AUC of4urglmUmin
DoxiUliposomal doxonrbicin: fiour 30 mplur2 to 24 mlt/m2
Epinrbicin if used in place of doxil/liposomal <toxorubicin: rvill be reduced by ?0% &orn 60 mglm2 to 48
rug/ur2. If epirubiciu is giveu in place or a dose-reduced dCIKil, fheu tlre dose-reduced epirubicin is to be
giva.
P*clitaxel: If pre-treatmeut PIUN <1000ftn1, do not re-ffeat uutil PMN >l000lb and platelet count
>100,0001d. tf r.o.r* neuhopenia occlr$ {Phrl}.{ <500/m' for 7 days), reduce subrequent doses-by 20Yo
{iom'gO mdm2 to 64 rng/m2. Filggasiim ruay be adde.d to the ueaturent regirueu per institutional guidelines
at the discretion of the teating physician-
Docetaxel: If severe neukopenia oecurs (PMI{ <500lml for ? days). moderate (grade 2} neruosensory. or
severeleumul*tive eutaneoris reaction, reduce subsequent doses by 25% &om 100 mglmn to 75 nrglnrl. If
AEs persirt: Re.dus* fiuther to 55 rug/m, or dicconfirue. Filgrastiru should tre g.iven with lhis regimen per
institutioaal grideline*. If p*tient t * C*O* 3 peripheral neuropathy: Discontinue. If patient has Grade 314
Stomatitis: Decrease to 75 mg/mr. Do not administer if ASTIALT >5 tiures ULN or alknline phosphatase >5
times ULN. Redrrce dose by ioo.t f *Sf/ALT >?.5 - 5 times ULN and alhaline is 2.5 times ULN or lowerl
alteruarively lower the dosi by 20ori, if AST/ALT > 1.5-5 times ULN and alkaline plrosphatase >2'5-5 times
ULN.
Abraxage: petients who experieoce severe neutropenia {neutrophils < 500 cellslmm3 for a week or longer)
or severe sensory neuropathy during Abraxane therapy should have dosage reduced ta 220 rnglm2 for
subsequelt "o*r*a 
of Abraxale. For recurrefice of sertere neukopenia or severe sensory neuxopathy.
additionsl dose leduction should be made fo tr80 mS/ur2 . For Grade 3 sensory neruopathy hold treatment
uutil resolution to Grade I or 3, followed by a dose reduction for all subseryreut cotuses of Abraxaoe.
Filgrastim may be ad&d to the trcahnent reginren per icstitutioual grridelines at the discretiofl of the treating
physician.
-?q-

No additional dose reductions rnay be given except as ildic*ted below for *pecific toxicities" If toxicity occltts
that would indicate a firther dose reduction is ueeded, the patient will be removed from tlre study. Doses,
which have beenrsduced for toxicity, must uot be re-escalnted with the exceptitrn of liver fimction tests thet
improve within ranger given.
7.4,1 Crrboplntin
Febrile Neutropenio
Febrile reufiopeoia shall be de{ined as oral or tympanic fever of } 38.5oC or 101.3"F in the prese*ce of
neutropenia (where usukqrenia is delined as ANC < 1000/nrmr). A tlrerapetttic intervention should proceed
immediately following tlre diagposis of febrile neutropeaia- Therepeutic interveutions can be as per the
institution's grridelfures, or may include:
r hospital sdeissiou
r pre-antibiotic evaluation
r CBC wi& differeutial and blood culture slrould be performed
r start of aa empirtcal antibiotic therapy
ln case of {bbrile neutropeuia, blood courrts n*rst be done every ? days uutil recovery of ANC } 1,000/mr:r3
or ornl tenrperattue < 38.5"C. This must be docrunerted in the specific adverse event section of tbe CRFs.
For the firxt episode! resume toeaheut at fir}l dose withpeg-filggsstim ({i-CSf} support. If despite peg-
filgrastim support a second eprsode occuxs dose reduce cartoplatin to 4 AUC and doxiVliposomal
dolonrbicinio Z* rnglm?. If a ttrird episode occur$ the patient will be taken off-strrdy. Peg-filgastim
support can be giverat the discretion of the heating physiciau for grade 2 or higher neutropenia in the
abse.nce of fever or infection.
Infection ltrith (or Without) Neutropcnia
For serrere (Grade 3) or life-&re*tening (Grade 4) iufection duriug chemotherapy, with or without
neuuoperia, praphyloctic 6-CSF nnd prophylactic anfibiotics will be addecl to all remainiug cycles.
tevofloxacinis iscouu$ended at 500 mg oral dose daily for l0 dayr starting on Day 5 of each cycte lbr
remairdsg chemotherapy cycles. If levofloxacin is not av*ilable or uot tslerated, anofher oral a$tibiotic
must be used. The ehoice of autibiotic is at the discretion of the luvestigntor. G-CSF will be added to all
subsequert chemotherapy cycles es per ASCO guideliues.
2nd Febrile Neutropcnin and 2ntl Infectiou Event
Iu the case of a second felrite neutropenia or infectiou eveot, patieut will cautinue with the prophylactic
6-CSF for all subseryrett cycles. In idditiou, all c.heurotherapeutic dnrg doses will be reduced for *ll
remaining cycles. In the case of a 3rd event, there will be ao further dose redtretion. The patieut will stop
carboplatin aad be renroved triurn the study.
Neutropeni* in the Abrence of Ferer of Infection
In case of neunopenia ia the abseuce of fever or infection. blood cotutfs urust be done evety 2 days rmtil
rccovery of ANi > l.{X}$lmm3. For the first episode, re$ume treatmeot at full dose with peg-filggnstim (G-
CSF) support. If despite peg-fllgrastim suppofi, a secoud episode occurs dose reduce earboplatin to 4
.AUC anddoxillliposomni doxorubicin to ja $#r#. If a third episode occurs fhe potient will be talrgn_ o{f-
study. Peg-filgrartim support can be given at the discretion of the treating physician for grade 2 or higlrer
ueutunpeuio in tbe absence of fever or infection.
-30-
Title: A Phase 2 trial of li
md carboplati[ in patients with ER- pR. HER2 negfiir.e breast cancer (TNBC)

Ancmin
In case of Grade 2 decrease inhenroglobin, heahuent with blood transfilsion should be given. The use of
prophylnctic erythropoietin is discoru*ged" In case of Grade 3 or 4 demease in hemoglobin, doses slorrld
be reduced as follows: cadrcptatin mduced &om an AUC of 5 m$nrl./min to an AUC of 4 m$mUuin.
Maintain the doxil/liposomal dsxonrbiciu or epinrbicin dose.
Ncusel rnd Vomiting
Antie!:netic prophyloxis is mandatary fbr all patients. Selectiou of anfisretics is st the discretisr of the
Irvestigator. Acute episodes of nausea andvomiting should be conholled with adequ*te antiemetics. Iu
ccse of-Grnde 4 vomitisg that persists despite nntiemetics, patient will discontiutre car.boplatin aud be
removed &om the study.
Oral Slurositis
In case of Grade 4 oral mucositis (andlor exoplragitis] thepatieut will disconlinue rarboplatin aod be
removed &om &e study.
Periphernl Neuroplthy
If the patient *xperiences periplreral neuropathy of Gr*de 3, the following dose urodi{ications shotrld be
perfonned: Delay carboplatin fueafinent by a maximtm of two weeks. As soon as patieut rec.overs,
treafineut shoutd continue with the following dose teconrmendstious:
r If patient rscovers to Gra.de I toxicify, maintain tlre carboplafin and doxiUliposom*l doxonrbiciu or
epirubicir doses"
r $Grade I persixts f,or > 2 weeks, patieff will discontinu* carbopl*tin and be removed &om the shtdy.
In case of a secoud episode, mniutaiu &e carboplatiu dose. If thr patieul experieoce.s another episode. uo
fruiher dose reduction is planced aud the patient will discontintre cartoplatin and be removed frour the
snldy.
Pstients who experierce severe peripheral ueruopathy while orr weekly paclitaxel should have dosage
reducedby Ztr/o for subsequent courses.
Cutsneous Re*ctions
. For 6rade 4: Fatieut will be takeu off-snrdy.
7.{.2 DoxiUliposomd doxorubicin
patierts shsuld be carefully monitored for toxicity" Adverae events, such as Pahnar-Plastat'
I.rythrodysesthesia Syndrome (PPE), hematologic toricities. aud ruucositis may be rnanaged by dose
deiays and adjustment. Follawiug ttre first appe$m$ce of a Grade 2 or highm adverse event, the dosing
sllould be *djusted or del*yed ss des*ribed in the following tsbles. Once the dose hes been reduced, it
should not be incraased *t a later time"
-tl -
Title: A phnse 2 trial of liuosornai doxorubiciu and cnrboplatin in patients with E& pR- HER2 negntive breart cancer (INBC)
I-I

Tfule: A Pbase 2 trial of lit
a$d carboplatin il} patierts with ER" PR. HER2 llBgati\ie breast cancer (TNBC)
OXAI, T{UCOSTTIS
Toxidtr Grade
Dose Atliurtmeut
I
(Asymplonr,atic or mild sylllptorlr;
fu teryeotion not fu rdicatcd)
lfo i[inge iu doselschetlule nnlest patieut has expedented 
-
prtvioufGl'adt 3 orI toxtcitl" If so, dtlay up to 2 weeks and
decrease doxildose by 30%. h{alltain the Carboplatiil
)
(Moderate p*iu not interfering with oral
intakel msdified diet fudicatd)
@ks 
or until rmolvrd to Grade 0-1. if tfter
? weeks there is uo resoltttiou. patient rtill be reuroved fl'our the
study. If resolved to Grnde 0-l wit[i1 2 week. and thrre was no prior
Craie lA mucositis. cotltinue trefitment al previott$ dose. If patimt
experience previous Crade 3-4 toxitity, continue temtil]ent widl a
?0-ori, doxil dose reduction lvt{ultah the Carbopla
3
(Severc pain; intufering rvitlt
oral intake)
Delay doslug up to I rveeks ot'ttutll resolved ts Grade 0-1.
Decriase doiit dose by 20%. L.Iailtain the Carboplatiu dose. If after
3 weeks tlrere is no resoluriotr, pafient will be rernoved ftom the
srudy.
4
(Life-tlueatening
c0nlequences; urgent
irteffenfioil indicated)
Dekt dosing np to 2 weeks ot'until rsolvr.d to Gr*de 0-l-
Decrease dose doxilby 30%. Maintain the Carboplntiu dose. If after
? weeks tbere is no resolutiotr, patient will be reruoved frour the
shrdy.
7.{,5 Paclitaxel
prtients should be assessed clinicalty for toxicity prior to, dluing, a*d a&er each inftBion' If mruanageable
toxicity occurs at any tirne duriug tle shdy, treatuant with paclitaxel should be discontinued. Side effects
requiring dose redgctiog should hsve dosage rednced by ?090. Side effects requiring dose reductions or delays
are described below.
Y S E STHE S L{ SYNDR0\4EE-qE}
Toxicity Grsde
Dore Adiustment
I
tMinirn*l skin efunuges or dermatitis
(e. g., erythema,edema. or hlperkeratosis)
rvithout pain)
No rhrngt ln dose/rchedule unlms pntleut h*s txperienced
predrus Grrdr 3 or { FPE" If rio, delay up to l weeks uid decreasc
doxil dose by ?0Yo.
7
(Skin churgrs (e.9., peelkg,
blisters" bleeding. edeum, or
hyperkeratosis) wi& painJimitittg
instnunental ADL.)
Deta]' d"ting up to 2 xeeks or tntll resolvtd to Grade 0-1. If after
3 weeks there is no resoltttiotr. patient lvill be rernoved frorn the
shtdy. If reso,lved to Orade 0-t rvithin 3 weeks, and there are no prior
Graie 3-4 PPE, coutfurue doxil treabnellt at previous dose aud retunt
to origiual dose inteival. If patient expedenced previous Crade 34
toxieitv, continue treatment with a ?096 dose reduqtion of doxil"
3
(Severe skiu changes (e. g,.peeli*g,
blistsrs, bleeding, edeme, or
hyprkeratosis)
with oaiu limiting self caft ADL)
Dda.v tto*ing np to 2 weeks or untll resolved to Gradt 0-1.
Decrisse doiil dose by 209'o ancl refirru to origital dose irterval. If
after 2 rvseks tltere is no resolutiou. doxil shoukl be discontinued'

Tirle: A pbase 2 trial of liposounl doxorubicig and carboplatin in patients with ER- PR- HER2 negative breasl cillcer (TNBC)
I-I
Neutropenie
Mailtail dose if lellrope$ia oscurs (gracle 2-4) buf recovers before the uext keatment. Hold paclitaxel
mtil > lo00ltxnl. If recovery takes: l-3 weeks - nraintain dose and add filgrastim. O*ly filprastirrr on
Days 2-6 m6y be u$ed for weekly pnclitaxel per h'eating physicinn discretioo: pegfilgrastjm is prohibited
du1ilg weekly paclitaxel, If receiving filgastim and recovery takes: I week - maintain ilose; 2-3 weeks
decrease one dose level.
Fehrlle Neutropenin
Febrile ueutropenia shall be defured as oral or tympanic Ibver of > 38.5"C or 101.3"F in the presence of
neutropeuia (wlere neuhopeuia is defined as ANC < 1000/nrnr3). A thernpeulic interveution should
pro*.*d iuuuedintely folo*ing the diagprosis of febrile ueutropenia. Therapeutic iuterve$tians cau be as
per tlre i&stihrtion's guid*lines, or rusy include:
r hospital adrnission
r pre-antibiotic evalu*tiou
r CBC with differential aud blood culture should be perfonned
o start of au ernpirical antibiotic therapy
In case of fe.brile neltropenie, blood counts must be done every 2 days tmfil recovery of Al'{C > 1,000/urm3
or oral ternperahre < 38.5oC. This urust be docruuerted in tlre specifie adverse event sectiou of the CR.Fs.
Wi& grade 2 infection, the dose should be maintaioed, but filgmstim grophylaxis added for subsequent
ch*mitherapy if neubopenia wa* preseat- For grade 3 infection or fbbrite neubopenia. maintain dose and
add fitgrgstim prophylaxis with subsequeut cheruofherapy cycles. If rsceivirg prophylactil {lgrastittr.
reduce"ole dose leril. For ggade 4 infbction or febrile neutropenia, maintaiu dose and add filggastim
prophylaxis with strbsequenichemotherapy cycles. If receiving prophylactic filgrastim, reduce one dose
i*'t *t Lr discontinuatioo. Ooly frlgrastim oa Days 2-6 may be used for weekly paclitaxel per treating
physician discretion; pegfrlgrastiru is prohibited duriag weekly paclitaxel.
Xnuses rnd Yomitirg
Antieruetic prophylaxls is rnandatory fsr all patieuts. Selection of antiemetics is at the discretiou of the
Investigetor. Acute episodes of uausea and vomiting should be controlled with adequate altiemetics. If
vomitiig is gade 2 despite antienretics bnt recovers before next dose, maintain dose or reduce by one
dose lev-el. If vornitirrg is grade ? despite autienretics but does uo{ recover before next dose, rnairrtain dose
or reduce by oue dose-- tevel. If vouritiug is grade 3 or 4 but recovers by the next dose, redrrce dose by oue
level or discontigue. If vomiting is grade 3 or 4 but does not recover by the next dose, discontiuue
paclitaxel.
Diarrher
For grade 2 diarrlrea t&at resolves prior to next cycle. maintain dose. However, for pade 3 that resolves
by nixt cycle, reduce by one doselevel. For grade 4 toxicify that recovers by next dose, reduce dose by
one level ar discoutinue. For prade 2 toxicitylhat does uot recover by next dose, either uraintair dose or
reduee by o1e dose level. Foi grade 3 toxicity that does not recover by uext dose, reduce dose by one
level. Foi grade 4 toxicity that does not recover by next dose, discortinue paclitaxel-
fuIucnritis
In case of Grxde ? mrrcositis that recoverx by uext dose, maintair dose. If it is ggade 2 but does not recover
by the cext dose" ei*er maiutaiu dose or r*d,r." dose by oue dose level. For grade 3 mueositis that eiflrer
recovers or does not recover by the next dose- reduce dose by one dose level. For grade 4 mucositis that
-rJ-

Title: A phase 2 trial of liposolral doxorubicin and cartroplatin in patients with ER- PR- HER2 treSative breasl cartcer (n'IBC)
IEI
recsvers by tle uext dose, rsduce dos* by ose level or discontirue paclitaxel. If a 6ade mucositis doe$
not rec,over lry the next dose. disconfiuue paclitaxel'
Thrombcytopeuia
If ptatelet cotirt is reduced (ggrde ?-3), mnintain dose. Hold rmtil > 75,0001mm3. If recovery takes: I week
mafutain dose; 2 to 3 weelrs decrease one close level. If toxicity is gpade 4, hold until ? 75,0001nrm3 and
decrense one dose level.
Hepntic Dysf,unction
Hepatic dy*frmctiou is defined as elevated bilirubh, A T or alkaline phosphatase. For gadl 2 toxicirv-
that recovers by next dose, reduce dose by one lsvel. For grade 2 loxicity that does not reeover by the next
dose, hold paciitaxel uutil bilinrbfur returns to tlre baseline grade and eS].and alkaline phosphatase have
rettrmed to S grade I and then reduce one dose level. For gratte 3 toxicity ihat recovers by rrext dose.
either reduce Jor* oo* level or discontintre- For ppade 3 toxicity that does not recover by the llext dose,
lrold rurtil bilinrbiu rehnus to the baseline gpade and AST and slkaline phosphatase have retunred to 5
pade I and theu reduce one dose level oi discontinue. For grade 4 toxieity, regudless of recovery'
discmtinrre paclifaxel.
Peripheral Neuropethy (paresth*ias or periphrral rensory nenroplthy)
Iftlre patient e*p*ri*o"., fertpheral nr,rroprtt y, Se following dose rccou$leudafioas shouldbe followed:
Grade t leruopatSy that is less thnn 7 days duration, uraintaiu paclitaxel dose' If grade -2, curreilt dose
m.ay 6'g naintaiged if inrproves to ggade f Uy a"y of keatnreut. However, for a grade 2 that persists > 7
days or delays next heatruent" deirease dose by one level. only firo dose reductions are allowed. If
peripheral neuropa&y worse$$ or persists despite tnvo dose reductiots, paclitaxel should be discottinued'
The Iirst episodeof gade 3 neruopa&y that rnsolvespriorts rrext dose wauants one level dose reductioo-
For the second episoae of gmdei that resolves or first episode.that-persists > 7 days or rvould delay
heatment or {ny ioa. + neuropathy, paclitaxe} shsuld be discor*inued.
Musculosk*letal pain not controUetl by cnalgesics (nryelgil or arthralgia)
For grrade I or 2 side effects tbat resolve days I-2, nraintairrpaclitaxel dose. For grade 2 that persists > 7
daysl uraintain dose or decrease paclitaxel dose by one dose. For the fir'st episode of pade 
-3 ueuropathy
that resolves in ? days or less, deerease paclitaxel by one dsse. For the second episode ofgrade 3 that
resoh,es iu 7 days, discorrtinuE"paclitaxel" For: gr*de iueuropathy that doel not resolve by 7 days, for fir:st
episode either d.*r.*" dose one level or discoutinue. For second episode, discoutinue paclitaxel- Hold
paclitaxel forpersirtcnr grade 2 cr 3 rnuseuloskeletal pain. When 5 Srade I' resume teatrl}ent with dose
urodification.if gr*de 2 ir grade 3 toxicity persists after 3 weeks of delay, discontinue paclitaxel'
Other Clinically-signilicnnt Adverse Events
For grade Z that resolves prior to fhe next treahuent, rnaintain close or reduce by one level' For grade 3
that resolves prior to the next treatuienf, reduce by one dose. For grade 4 that resolves prior fo the next
treatment, uujo"* 6y one dose or discontfu:ue. Fof grads 3 that requires delay of therapy, reduce by one
dose or discontfuue. nor grade 4.dmt would require dase delay" discoutinue paelitaxel'
7.,t.3.1 Iafusion Reaction
Inftisiol of paclitaxel should be intemrpted for patieuts who develop dyspreaor clinically significant
hlpotension. patients rvho experience a NCI CTCAE v+.0 Grade 3 or 4 allergic
renctiou/typelsensitivity, a&rlt respiratory distress syudlome, or lnouchospasur (regardless of grade)
will be discontinued &om paclitaxel treahnent-
-14-

Tirle: A phase I trial of liposomal doxorubicin and carbaplatin in patients urith ER" PR- HERI negntive breasl cancen (I}'IBC)
I-I
The inftwion should be slowed to 50?[ or less or irteffryted for petients rvho experience aCIy inftlsion-
associated syurptoms not speci{ied above" Wheu the patienf's syaptoms have conrpletely resolved.
the infusion'may be coatisued at uo nrore dlar 500/6 of the cun'ently beilg received ytg frior to the
terctior and increassd h SSBI iuuements every 30 minutes if well tolerated, Iufusiotrs may be
restarted *t the firll rate &riug tlre next cycle'
7.{.d Epirubiciu
lrthe evslt that there is a shortage of doxiVliposorual do,xorubicin, pntieots will be allowed to reeeive
teailneut with epinrbicin" Treanuent rvith epinrbicin is allowed if D0Xlllliposomal doxorubicin must
be dircontiuue-d due to toxiciry at the treatingphysiciau's dissretion.
Diarrhea snd Mucositis
Antidiarrheal medication may be used at the discretion of the Investigator, Diarrhea and mucositis must
retum to < Orade 1 before stlministretion of the next cycle. If, after a 2 week delay, diarrhea and/or
mucositis have not resolved, thempy nrust be discsntinued.
Crsde I nntl Grsde 2; No dose reductions.
Ggde J: After the first episode of Grade 3 diarrhea and/or mucositis, de,crease the epirubicin dose to
aB mglmP. Mail$nin the carboplatin dose.
Grnde 4: If tlre patient experierrces Grade 4 diarrhea and/or mucositis, therapy urust be discontinued.
Hepatic Ilysfunctian
Tlerapy mist be held for a l Grade 2 ircrease in biliubin {>1.5 x ULN) or Grade 2 increase h} 560T
p LS ; UIN). If flre irrcrea*e is rot due to setastatic disease. ther*py may be resumed at firll dose if
the lbllowing criteria xre ulit:
r SGOT mnst rehrm to < grade ? E 2.5 x IlLt{) within 2 weeks; and
r Bitirubin unxt retmn to nonnal rauge for the lab within 2 weeks.
7.5 Concomitrnt Medicltions
In general, concornitant medications aud therapies deeured nece$saly for the supportive care and^*afety of
&Jpatient nre allowed. All concomitant medicationsmustbe doct'meutedinthe patieut's mediealrecords.
?.6 $upportiv* Cnre Guideliner
AU slrppo*ive measgres consistert with optinral patient safety will be utilized, includi[g but not lirnited
to antieruetic medication. fuydratiou, trausfilsion support and autibiotics. Peg-filgrastiur may be.given as
support with liposornal doxorubicill and carboplatirwhile filpga*tirn uroy be given as support with lveekly
paciitaxet at the disgetion of the treating physician. No other chemotherapy, irnmrmotherapy, radiatioa
th*r*py, sursery for caocer, or experimental medications will be permitted while the patieuts are
participating fu dli$ stra*Y.
Use of G-CSF or eqgivalent is to be used in accardance with ASC0 Guidelines and s* ifldicated nbove.
--15-

Title: ,t Phme 2 trial of liposonral doxorubicin and rarbcplatin in p*tieds with E& p& HER: negative brea$i cancer (I].IBC)
INI
7.7 AdhsrencelComplirnce
Pafients who fail to present for kealurent appoiutmeuts may be removed froru the study. Patients that are
roufinely non-compliant to protocol rcquirements umy be reuroved at the discretion of the Investigator.
8. Toxicity lllonitoring *rd Adverre Evcnt Reporting
All patieuts who fisceive one dose of profocol &*rryy will be evaluable for assessmeut of toxiciry. Prior to
each cycle the treating physiciau or 6eir dssignee *"in n*ry a$$e$s the patieut's condition with rerpect to
possible heatment related toxicities. All adverse events, whether obserred by tbe physician or repoited by
the patieut occtnring during the active portiou oftherapy, or trp to 30 dayr aftei the tasidose of keatment wiil
be graded by a utuuerical score accordiug to tbe NCI's Cournron Tenniuology Criteria for Adverse Events
(CTCAE), vErsion 4.0 (bttp;llqtep.cnqqer.spv/reipor"tindctc.htull) aud recorded in the patient's ruedical
record. Toxicities (irrcludirg laboratory abnonnalities) will be reported as outlined iu the dsta caphre plan.
A preexistiug conditiou is oue that is present at the stari of the shrdy" A preexisting c ndition will be recorded
as au adverse evert if the &equency, inteusi$, or the character of the condition worsea$ dtring tle shrdy
period.
8.1 Adverse Event Reporting Requirernents
Au adverse experience is detined as auy trtrirrteoded or abnonnal clinical observation that is not of benetlt
to the patient. Either the couditiou was not prcsent prior to exposru€ to tlre study therapy, or it has
worseued ia intetsity or fr*quency following expCIsme to the shrdy thernpy.
All'tmexpected" and/or "seriou$" edverse eveuts occurriug dlring the sctiye portion of therapy, orup to
30 days after the last dose of treatmsnf, will be reported to tlre OHRS at (732) 235-757V or (?32) 235-
8675. Events will be promptly rcported, in writing, to the local IRB in aecordalrce with IRB policy. If a
deafh occtus the IRB will be notilied witldn ?4-horu"s cf initial receipt of infonnation. All other $AEs
uust be reported to the IRB within tluee to ten days of iuitial receipt of infonnation. Written follow-up
reports are required when additioual informafiou is needed to flrlly characlerize the event. Copies of each
report s.ent io the IRB will be kept in tlre study repnrlatory file.
Reporting 8A& uring commercislly tveilnble drugs:
In additiorr, any uaexpected (nol listed in the package insert) serious adverse events that are associated
(definitely. probably or possibly related) with the use of doxil'liposonral doxorubiciu and carboplatin or
paclitaxel must be reporled to the FDA withiri ? working days using a FDA Fonn MedWatch 3500 forur
http :frvww. fda. gorlmedwft tch/safety/3 5 00.pdf (fax # t - 800-FDA-0 I 7 8)"
Expedited reportiug requirement for adverse events experienced by patients heated with
gqrn4qercial agents only
Amibution
Grade 4
Grade 5"
Protocol Specific
Requirements
Unexpected
Expected
Unexpected
Expected
Uruelated
or Uulikelv
Possible,
Probable,
De{iuite
REPORT
REPORT
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Tirle: A phnse 2 tial of lipqsatuat doxorubicin urd c*rboplatin fur patiarts with ER PR. HER2 negative breast cancer (TNBC)
INI
FDA Medlilntch form 3500: Indicates that an expedited report is to be submitted to the
FDA rvithin 7 worki
a: This ineludes sll deaths within 30 days of the last dose cf treat*rent with a comurercial
agent(s), regardless of nthibution. Any deoth that occrus more thao 30 days after the l*st dose
of treatrneut with a conrmercial agent(s) and is attributed (possibly, probably, definitely) to the
agent(s) and is not due to cancer recuneilce lnust be reported according to the iustnrctions
above.
fi.2 Delinition of Striour Adversc Evrntr (SASr)
A serious adveme eveut (experierce) is one occtrring at auy dose level that resnl* in any of the
following outcomes:
r Dealh
r tife-trreatening- irrrrnsfinfs risk of death frorn the reaction.
r Requires inpctient hospitalization orprolougatiou of existing hospitalization-
r Results in persistent or sigrrificant disabilitylincapacity.
r Results iu a congenital alromnlylbirth deiect.
r Requires intBrveution to prevent one of the outcome$ li*ted in this defitition.
Tlre definitiou of serious adve,rse event (experterce) also inclnde s inryortant medical ewnts. Medical aed
scientific judgrnent will be exereised in deciding whelter expedited reporting is appruprtate in ofher
situalions, sueh as inrportant rrredical events tlrat nray not be iuunediately life*hreatening or result in death
or hospitalization but may jeopardize the patient or ulay require intervention to prevent one of the other
outcomes listed iu the defhition above. These events will usually be considered serious. Exaarples of
such eve;1ts are intensive treatnent in au emerg*ncy room or at home for allergic branchospasrn; blood
dyscrasias or couvtilrions that do not result in lrospitalization.
Hospitalizatiou that do not mee,t this criteria are:
. rea$ors described in the pratocol, e.g. druS adrninistration, ptotocol-required testing
r socid reassr ia the abseuce of an AE
I surgery or ptocedure planned prior to entry into the study
8.3 Delinition of Relstcd
There is a reasouable pos*ibility &at the drug caused fhe adverse experimce. Thnt is, the event is judged
by the iuvestigator to be possibly, probab$ or definitely related to the treatment"
8.{ I}cfinition of Unexpected
Any adverse dnrg experience andlor specificity, that is not included irr the current iuvestigator's brochure
andlor p*ckage itsert.
9. Trestmout Evdu*tion/Criteris for Besponrr
9.T DOCUMENTATIOIi{ OT BREAST CANCER RECURRENCE ANI} $ECOND
MATIGNANCIES
r Docmrentatisn of a bresst caltcer recuffence requires ureetiug at least one of the criteri* defmed
below. Suspicious findiugs do not provide adequate document*tiffr of a breast ca$ser recurrence
and should not be au indication to alter protocol ther*py.
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