A Phase II Trial of Doxil, Carboplatin and Bevacizumab in Triple Negative Previously Untreated Metastatic Breast Cancer
Phase: PHASE2
Conditions: Metastatic Breast Cancer
Sponsor: Rutgers, The State University of New Jersey

Official Title:
A Phase ltTrial of Doxil, Carboplatin and Bevacizumab in
Triple Negative Previously Untreated Metastatic Breast
Cancer
NCT number:
NCT00608972
Document Type:
Protoco! #1
Date of the
Document:
LOlLT l2OL3

A Phnre II Trial of Dcxil, Curbaplatin snd Ber,*cisumab iu Triple Negntive Proviously
Untrested Mettststic Breast Cancer
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A Phase II Trial of Doxil , Carboplatin afld Bevacizrulab in Triple Negative Prelio[sly Ufltreated luetastatic Breasl Cancer
TABLE OF CONTENTS
1. 
PURPOSE/SPECIFTC OBJECTIVES................... 
........................5
2. BACKGROIJND AND SIGNIFICANCE..,,.... 
.........5
3. PARTICIPATING INSTITTTTIONS............
4. EXPERIMENTAL DESIGN AND METHODS
5. PATIENTSELECTIONCRITERIA.
....9
5.3 INCLUSToNoFWoIGN AND}{nonrrms 
...................11
5.5 Soutcss onMrrnoos or RscRumvcr+r 
.................11
6. STI'DY PARAMETTRS
7, TREI\TMENTPLAN..........
....14
8. TOXCITYMOI{ITORII{GANDAI'YERSE EVENTREPORTII{G
27
8.1 AD\ERsEEvEr,[TR.eorrwcRrgr-m.sur4rrs.................... 
.............28
8.2 Dsrarmox or SEnrorx Apvsnsr Evnrrs (SAEs).......... 
...............30
9. TREATMENT EVALI,]ATION/CRITERIA T'OR RESPONSE............. 
.........31
10. REMOVAL OF PATIENTS FROM STUDY/OFF STUDY CRTTERIA
.....35
11. LABORATORYEVALUATIONS
...........36
12. PIIARII,IA,CEUTICAL NFOR\{ATIOI{ ..............
12.4 Epnusrctr{HyDnoctroRoE@urNcrru). 
...........................42
13. DATA COLLECTION AND RECORIIS TO BE KEPT".......... 
-.....,...'............,13
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A phase II Trial of Doxil , Carboplatin ancl Bevaciannrab in Triple Negative heviorsly Untreated N'Ietastatic Breast Cancer
13-2 DATASrBrvffisroNTnreLBIE AND Fonus.......... 
.....'...'.'.'.'.'...'.'...'14
14. DATA AlsD SAf'ETY MO]'iITORING...................
15. MTILTT-rrrsrrrurIoNAL GttrDELBIEs {E.G., CNJOGTRIALS}.................. ................45
t5-3 IRB CorsronmrcApmovrrs 
......'....45
15.6D.uaCou.scroxar.ro ToxctrvRrpoRrnqa.... 
.'.'...'...'...'.'.'...'.'45
15.7 Dara.MoxrronnvcAND Sot RcEDocuMn.rrVrnmcenoN 
.......46
16. STATISTICAL CONSIDERATIONS........, 
...........46
17. ETIIICAL AND REGULATORY CONSIDERATIOIiS
.,...,41
17.2 hvsrnmoNar,RsvgwBoARD Appnover^.... 
-.-...-.47
18. HUMAN SUBJECTS
........{9
19. ECONOMIC/FINAI'iCIAL CONSIDERATIOT{S
20. PUBLICATION OF RESEARCH FINDINGS..
...........50
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A Phase II Trial of Doxil , Carboplatin ald Bevacizrunab in Triple Negative Preliotsly Untreated Metastatic Bteast Carcer
LIST OF ABBRIVI4,TIOIiS
AE
ANC
BUN
CBC
I
CT
CR
C]RF
CTCAE
DSMP
ECG
ECOG
FDA
HHS
IRB
kg
nrI
NCI
NIH
OI{RS
OHRP
PBMC
PD
PFS
PHI
PI
PR
R\I/IUH
SAE
SD
sCr
SGOT
SGPT
ULN
Adverse Event
Absolute neutrophil count
Blood urea nif,ogen
Couplete blood count
Computer Tomopraphy
Complete Respouse
Case Report Fotm
Conrmon Tenninology Criteria for Adverxe Events
Data Safety Monitoring Plan
Electrocardiogftutr
Easter:r Coopemtive Oncology Group
Food and Drug Adrninisftation
Department of Health and Human Serices
Institutional Review Board
kilopranr.s
milliliters
National Cancer Institute
National hrstihrtes of Health
Office of Human Resealch Services
Offlce oiHuuan Research Protection
Peripheral blood mrrnonuclear cells
Progressive Disease
Propressiou Free Stuvival
Protected Health Informatiou
Principal Investigator
Partial Response
Robert Wood Johnson Uuiversity Hospital
Serious Adverse Event
Stable Disease
Serrun creatifline
Senun glutamic oxaloacetic trausarnirnse
Serum glutamic pytvic transarninase
Upper limit of nonnal
I 
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A phase II Trial oiDoxil , Carboplatin and Bevaciauuab iu Triple Negative Preliorsly Untreated il{etastatic Breast Caocer
1. Putaose/Specllic Objectlves
1.1 Primary Endpoint
The prinrary objective of this sftrdy is lo detenuine the ruedian progession free survival
eFS) and l-year PFS after: heatruent rvith doxil, carboplatin and bevaciaunab in patients
with ER, PR, HER2nez negative metaslatic breast cancer.
1.2 Secondary Entlpolnt(s)
1.2-l To detennine the response rate (as deteuniued by RECIST criteria) to
combiuation therapy with doxil, carboplatin and bevacizunab in patieuts with
metastatic breast caucer.
1.2-2 To determite the toxicity of cornbirmtion theapy with doxil, carboplatin, and
bevacizumab.
1.2.3 To meastue tirne to event efficacy variables including:
. tiure to prcgressive disease
. survival time
L.2.4 To perfonu molecular analyses of archived hunor tissrrc to identify potential
rnarkers of response or tesistance to therapy.
2. Background and Significance
Approxiruately 215,000 new cases of breast carcer were diagnosed in the United States fu 2004
a1d ^43,000 died fiom this disease. Single agent or cornbination cheruothetapy produces
respolse rates of 40-70% in the treatrneul of advanced breast calcer. Although rumelous
regimens are effective in palliating symptoms arrd inducing ttuuor regression, the conrplete
t€sponse mte is less than 20-qlo. Moreover, the median duration of response is nine months with a
median survival af 12-24 months. Thus, most responses are of limited duration and nearly all
patients with stage IV disease eventually die of disease pragtession (1). Therefore, the ffeatment
of patients with metastatic and locally adwnced brcast cailcer wan'ants investigation of novel
therapeutic strategies includirg more rational design and sequencing of combination
chenrotherapy r e gimens.
The choice of cancer ehemothempy is usually ernpilical. based more oil the histological
appearance of tlre huuor tlran on an uuderstanding of &e molecular detenninants of drug
sensitivify. This may account for the suboptirnal respouse rates in many treated patients.
Receutly, new moleculady-targeted, non-cytotoxic therapies have ernerged as an option for
treatment of a select set of maligrrancies, whereby inhibition of a patholoppcally-sipificant
nrolecular target is thougfut to be respousible for disease legpessiott. Givet the comparatively
non-toxic characteristics of these rnolecululy{algeted pbannacotherapies. a logical oext step ir
the search for morc effective chemotherapeutic regimens is their corubinatjou with standard
cytotoxics.
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A Phase tI Trial oiDoxil , Carboplatin ald Ber,aciauuab in Triple Negative Previotsly Untreated l\,Ietastatic Breast Cancer
One such biologic agent that has de.monstrated significant activity in breast carcer, is the
antiangiogenic agent. bevaciztunab. a htunanized monoclonal antibody directed to vascular
endothelial growth factor. Compoturds targeting angiogeaesis are of particular interest as
extensive laboratory data suggests that angiogenesis plays au essential role in breast caucer
development, invasion aud metastasis.
Hyperplastic mru'ine breast papillomas (2) and histologically nonual lobules adjacant to
cancerous breast tissue (3) supporl angiogenesis in preclinical nodels suggesting that
aogiogenesis plecedes transformation of Dlammary hyperplasia to maliguancy. Transfection of
hrmor cells with angiogenic stirnulatory peptides sucb as fibroblast grorvth factor-l or -4 (4,5) ,
vascular enclothelial growth factor (VEGF) (6.7). or progelatirrase-B (rnahix metalloproteinase-9,
MMP-9) (8). increases trmror growth, invasiveness, microvasculafure and rnetastasis (9).
Converssly, transfecliorr of hnnor cells rvith inhibitons of angiogenesis, including
tluombospondin-l (10) or tissue inhibitor of rnetalloproteinase-4 (TIMP-4) (11) decreases
growth ald uretastasis (12). Clidcopathologic conelarious also confuru the central role of
angiogenesis in breast carcer progression. Fibrocystic lesions rvith the highest vascular density
were associated with a greater risk of breast cancer (13). Two distinct vascular pattems have been
described in association with ductal carcinoma in sinr: a diffirse increase in stromal vascularity
befiveen duct lesions and a dense rin of microvessels adjacent to the basement merubrane of
iudividual ducts (14,15). Microvessel density (N,{VD) was llghest rvith lustopathologically
agpgessive DCIS lesions and rvas associated with increased VEGF expression (16).
Recoguitiou that angiogenesis is esseutial to the growth of solid turuors (17) has led to
identification of angiogenic factors responsible for stirnulating nerv blood vessel formation. Of
the ideutified augiogenic factors, vascular endothelial grolvth factor (\EGF: also knowu as
vascular penneability factor) is the most potent aud specific and is a cmcial regrtlator of both
nonnal and pathologic angiogenesis (18). \EGF expression is regulated by hlpoxia via
urolecular pathways similar to those regrrlatiug erytluopoietin geue expression. The biologic
effects of VEGF arc mediated tluough biuding and stinrulation of nvo receptors on the surface of
endothelial cells. Flt-l (fins-like tyrosiue kinase) and KDR ftinase domain regrou). Though
multiple angiogenic factors are coilrrotlly exprcssed by invasive humau breast cancers, the l2l-
arnino acid isofonn of \{EGF predominates (19). Several srudies have found an iuverse
corelation betweeu VEGF expression and overall suryival in both nodepositive and node-
negative patients (?0-22). Eppenberger confinned the negative progrostic value of VEGF
expressiorr for both relapse and survival (23).
hrhibition of VEGF usilg an anti-\rEGF fironocloral antibody blocks the gtowth of a nusrber of
human carcer cell lirres in uude nrice including non-surall cell hurg caucer (Calu-6), colorectal
cancer (LS174T, HM-7, LSLiM6), brcast cancer (MCF-7. MDA-MB-435), prostate cancer (D-
145). head aud neck caocer (IG), aud ovarian cancer (SK-OV-3) (18.24). In addition, the
cornbination of auti-VEGF antibody aud cheurotherapy in nude mice iujected rvith hurran cancer
xeuografts resulted in an incrcased antitumor efTect corupared rvith antibody or cheurotherapy
treatment alone (25). A recombinant htunanized version of a mtuine anti-human VEGF
ruonoclonal antibody, named bevacizrutab Sevacianmab, Genenteclu South San Francisco), has
been created for clinical rue (26).
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A Phase II Trial of Doril , Carboplatur and Bevacianuab in Triple Negative Previously Untreated lWetastatic Breast Cancer
Moreover, prtclirrical shrdies have deuronstrafed the courbimtiou of cytotoxics with
bevacizurab to be syiergistic (27).
Tlre activity of siugle ageuf bevacizrunab in the metastatic setting set the fi'aurework for the
desigu and implementatiou of a phase Itr trial of weekly pacliraxel versus weekly paclitaxel plu
bevaciztunab as fust line therapy for locally recument or mefastatic breast cancer (E2100). The
results of this shldy demoustrated a sippifieantly irnproved 5 rnonth pragression free sruvival and
a doubling of the response rate from L4% lo 28% with the addition of bevaciaurrab to paclitaxel.
The impressive tesults of this trial have established bevacizumab and weekly paclitaxel as the
uew standard to which fuhue up fiont ruetatstatic regimens rvill be couipared (28).
BEVACIZUMAB CLINICAL EXPERIENCE
Bevacizttmab has beeu shrdied in a mulfitude of Phase I. tr, aud III clirrical tials in urore tharr
5000 patients and in multiple tumor types. The follorviug discussion sruruuarizes bevacizumab's
safety profile and plesents soure of the efficacy rcsulls pertilent to tius parlicular trial. Please
refer to the bevacizurnab Investigator Brochure for descrrptions of all corupleted Phase I,II, and
Itr hials reported to date.
In a large phase Itr shrdy (A!1F2107g) in patie*ts with metastatic colorectal cancer, the addition
of bevacizuntab, a mouoclonal antibody directed against vascular endothelial growth factor
O/EGF), to irinotecar/S-fluorcuacilileucovorin (IFL) chemotherapy resulted in a clinically and
statistically sigrrificanf increase iri duration of survival, with a hazard ratio of death of 0,67
(median survival 15.6 vs. 20.3 rronths: p < 0.001). Similar iucreases were seen in progression-
free stuvival (6.2 vs. 10.6 uronths: p < 0.001), overall respoilse rate (35o,/o vs. 45%; p < 0.01) and
duration of respouse (7.1 vs. 10.4 ruonths; p < 0.01) for the combiuation ann versus the
cheurotherapy orrly ann (bevacizrunab htvestigator Brochtue, October 2005).
Based on the suvival advantage demonstrated in Sflrdy A\IFZl07g, bevacizuuab r,vas desiguated
for priority review arrd was approved on 26 Febnrary 2004 in the United States for first-liue
treatrnent in corubination rvith IV ,5 FU based chemotherapy for subjects with metastatic
colorectal carcer.
2,1 Supporting Data and Rationale
The heahreut paradigur in breast cancer, holever, is evolving fi'om an eurpiric approach to a
more targeted one in which a particular brcast cancer phenotype is identified that is rnore
likely to respond to select combirmtion rcgirneus of biologics aud chemotherpay.
Breast cancers sre represented by a heterogenous gloup of ftunors, characterized by a wide
spectrum of clinical, pathologic and ruolecular feahrres (29-3I). This wide spectnur of
factors accotutts for variatiors fur response to therapy and otrkomes anong women diagnosed
rvith breast cimcer (32-34). Routine clinical variables such as prirnary tuuror size. uodal
stahts. age, aud honnonal recepfor staflr have more receutly been courplemented by more
extensive molecular profiling in an attempt to refine prognosis and response to therapy (35-
38). There have been ilumerous repofts denronsh'ating that breast ftunorc rvill segregate iuto
prognostic categories based on hierarchical cluster analysis of gene exprcssion profiling
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A Phase II Trial olDoxil . Carboplatin and Bevacianuab iu Triple Negative Previously Uutreated Metastatic Breast Cancer
(29,32,37,39-42). These tmique moleculil pattems can help gnride clinicians regardhg both
proguosis aud response to therapies.
Recent atteution has been devoted to a classification system rvhich employs three conunotly
available urolecular tuarkels, estrogen receptor, progesterone receptor and HER2r eu ald
classifies patients into srrbtypes pruniual, HER2rer and Basal) (30,32,34,43). Lruninal
subtypes make up the hormone receptor exprcssing hunorc aud cany a favorable proguosis.
These ttuuors have gene expression paffems which are siruilar to the lurninal epithelial
component of the bteast and genes associated rvith eshogen receptor activation. HER2
subtypes refers to the group of honlone receptor negative hunors with a speci{ic gene
expression pattem. Although not all fiunors which are HER2 positive by clinical testing
(imnrunohistochernistry anrVor fluorescent in situ hybridization) strictly t'all iuto this
category rnost HER2 positive tmnors would fit this criteria (30,32,34). While these tumors
are generally receptor negative aad cany a poorel progrosis than luninal types, the
et-fectiveuess of h'asfuzrunab in HER2 positive patieuts can significantly irnpact on the
outcorues of these patients (44).
Basal-like tuurors lack both hornone rcceptor aud IIER2 expression, and despite having a
poor pro$losis, these fumors hal'e been slnwn in neo-adjuvant shrdies to be responsive to
cheruotherapy (30) Basal type hlmors have been sho*,n to be urore aggressive, ar€ more
cornmonly seen in Africat Alterican womeu and are conmtonly seen in wornen who are
BRCAI caniers (30.32,40,4-5.46). While this classification systeur is based on tlre urore
complex and extensive genetic profiling assays, the simplified rnethod of classificatiou based
on the uriversally available and cormronly employed ER, PR and HER2ner clilical assays
make this system appealitg and clinically trseflll. Accordingly, cli:ricians are utilizing the
corubination of ER, PR and HEPCne:r- to classifo patients into these subtypes and are
increasingly utilizing "Triple Negative" (ER-. PR-, }IER2-) il clinical decision uraking and
protocol design. Receut data using more exteusive inununhistochemical staiuing and gene
profiling sfudies have demonstlated that these "basal-like" cancers are nlole commonly
positive for HERI expression, basal cytokeratins and c-Kit (29,36.40). These hunors also are
charactedzed by low exprcssion of BRCAI aud this phenotype is common among BRCAI
caniers and sporadic trunors that resernble tumors in BRCA1 caniers (45).
Therc are prcelincial and cliaical evidence demonsfi'ating that loss of BRCAI f,urction
predicts response to select chemotherapy agelts (47). fudeed. a retrospective review of the
literahre exarnining the futteraction of BRCAI and rcsponse to chemotherapy suggests that
the presence of a BRCAI nrutatiol confers increased sensitivity to DNA damaging agents
including topoisomerase poisons and platimrm-based compormds aud lesistance to the
spiudle poisous.
These data have lead to the desigu and implernentation of several shrdies in the "tiple
negative populatiot" utilizing platinunr based regimens as well as talgeted agents against
EGFR. These preclinieal and clinical data provide a sh'ong ratiouale for piloting the
combination of doxil. carboplatin and bevaciarmab in patierrts rvith previously untreated ER,
PR. and lIER2ner negative breast carcer. The combinatiou of doxil and carboplatin has
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3.
A Phase tI Trial of Doxil . Carboplatin and Bevaciauuab in Triple Negative Preliously Uuheated l{etasratic Breasr Cancer
been slrcwn to be a well tolemted and active rsgirnen in patients with advanced ovarian
carcer (48,49,50). Giveu the activity of both these ageuts in patients with breast cancer, we
postulate this will be a very active regimen r.vhen combined tvith bevacizumab in the upfront
metatstatic setting iu the tliple negative breast cancer population which cuueutly has no
def,rnitive standard of care treabneut regiruen. Patients are treated rvith the usual breast cancer
regimens. Doxil was selestetl as the prefered autluacyline given the increased cardiac
toxicity obsered in a small phase II sfudy of doxorubicin and bevacizumab in patients with
ruetastatic sot-tissue sarcomas (51) corupared to doxil and bevacizumab in sarconas (52)
and the reduced cardiac toxicity and comparable eflicacy of doxil versrx doxonrbicin
reporled in a phase Itr trial in r,vornen with nietastatic breast cancer (-53).
2.2 Availability of Doxil
When there is a shortage of Doxil at the 
, patients will
be allowed to receive xeatment with epirubicin, an altemative antluacycline. Treabnent
would theu consist of ryirubiciri (60 urg/mz), carboplatiu (AUC 5) and bevaciauuab (10
mg/kg) in patients with ER, PR" HER2rrez negative ntetastatic breast cancet'.
The patierit will coutinue to follow all requilenrents per protocol guidelines.
Particlpatin g Institutions
4. Experlmental Deslgn antl Methods
This is an open-label, rnulticenter, Phase tr trial to deter:nine the nredian progression free
sruvival (PFS) and i-year PFS after teatmerrt rvith doxil, calboplatin and bevacizumab in
patients with ER. PR HER2rrer negative metastatic brcast cancer.
To assue cardiac safety of the combination, initially 6 patients will be emolled. Assessmeut
of cardiac function will be made after 3 cycles. If one or rnore cases of CIIF are obseled,
accrual to the shrdy will be stopped. Approxiurately 50 patients are expected to parlicipate irr
this 2 year sftrdy.
5. Patient Selection Criteria
5.1 Inclusion Criteria
A patient is eligible for enrollment if all of the following inclusion criteria are met.
5.I.1 Women with previously urtreated ruetastatic lrreast caucer, EN?WHEP.2lneu
negative. Prior treatment il the adjuvant settiug is allowed.
5.1.2 Age >18. No upper limit.
5.1.3 Negative serun or urine B-hCG preguarlcy test at screening for patients of child-
bearing potential.
5.1.4 Patients with reproductive potertial must use arl adequate coutracqrtive method
(e.g., abstinence, intrauterine device, oral contraceptives, banier device with
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A Phase II Trial of Doxil . C:arboplatifl and Be$aciauuab in Triple Negalive Previo$ly Untreated N{etastatic Breast Cancer
spennicide or sugical stedization) druing freatment and for tluee mouths after
completing fueatmeut.
5.1.5. Patients must have an ECOG perfomatrce stahrs 5 2 (Appendix A).
-5.tr.6. Life expectancy > 12 weeks
5.1.7. Patients must have nonual organ aud marrorv fiurction as defined below:
. ANC Z 1.500 cells/nuu3
. Platelets > 100,000 eells/mru3
' Hemoglobiu > 9.0 g/dl-
. creatinine < 2.5 mgldl-
. Total bilinrbin < 1.5 X upper limit of nonnal (tlLN)
'ASr(sGorvf*t::J3';"1i,:,XJX:::lHiYiTr,a*dtotarb,irubin
urustbe<3XULN
5.1.8. Patients must have nomral cardiac frurction. as evidenced by a left vent'iculal
ejection fiaction (LVEF) within institutioual normal limits. Echocardiogmm may
be used if MUGA scar is uot available, but the same test must be rrsed throughout
the srudyto evaluate LVEF.
5.1.9 Irsion Eligrbility:
o Patients must luve documented meanuable disease as defined by RECIST
criteda (see Sectiou 9). or
0 Bone-only disease
5.1.10 Pafients may not receive concurent h'eatrnent rvith other investigational or
commercial agent(s) or have received aly other invesdgatioual agents withiu 28
days of the first day of shrdy dnrg dosing, other than a Genentech sponsored
bevacizumab cancer shrdy.
5.2 Exclusion Criteria
A patient will not be eligible for this study if any of the following exclusion criteria are
met.
5-2.1 Wonren rvlro arc pregrant or breastfeeding.
5.2.2 Second pdmary malignancy except most situ carcitoura (e.g. insitu carciuoma of
tlre of the cervix, adequately treated non-mel*nomatous carcinoma of the skin) or
other rualigmncy treated at least 5 years previously with to evidence of
lectur"efice.
5.2.3 History of hypu'semitivity reactions attributed to a conventional formulation of
doxonrbicin HCL or the cornponents of DOXIL@ or kaown hyperserxitivity to
auy cornponeut of bevacizumab.
5.2.4 Serious concomitaut systemic disorders (including active infectiols) that would
compromise the safety of the patient or compromise the patient's ability to
complete the sftrdy. at the discretion of the investigator.
5.2.5 Myocarclial infarct or urstable angina withirr 6 months before enrolhuent" New
York Heart Associatiorr (NYH.A) Class II or gleater heart faihu'e See Appendix B,
uncoutrolled angira, severe urcontrolled venhicular antytluuias, clinically
significant pericardial disease, or eleckocardiographic eviderce of acute ischemic
or active conduction systern abnonnalities.
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A Phase II Trial of Doxil . Carboplatil zurd Bevaciamrab irr Triple Negative Prelio[sly U[treafed Metasmtic Breast Cancer
5.2.6 Frior anthracycline dose exceeding 360 mg/# for doxonfiicin (including
DOXIL) or720 mg1m2 for epirubicin.
5-2.7 Inadequately controlled hlperlension (defiued as systolic blood pressrue >150
and/or diastolic blood pressure > 100 rnmHg on anfihlpedensive medications)
5.2.8 fuiy prior history of hypertetsive crisis or hypertensive encephalopathy
5.2.9 Knowu CNS disease
5.2.10 Siguificaut vascular clisease (e.g., aortic aneuysm. aortic dissection)
5.2.LI Symptoruatic peripheral vascular disease
5.2.1? Evidence ofbleeding diathesis or coagulopathy
5.2.13 Major surgical procedrue, opeu biopsy. or significant traumatic injtuy within
28 days prior to study enlolhuent or anticipation of ueed for ruajor stugical
procedurc during the coruse of the study
5.2.L4 Core biopsy or other urfuror surgical procedure, excluding placement of a vascular
access device, within 7 days prior to shrdy enrollment
5.2.15 History of abdomiual fistula, gast'ointestinal perforatiou, or iutra-abdonrinal
abscess withirr 6 ruonths prior to shrdy eruollment
5-2.16 Serious, nou-healing lvorurd. ulcer, or bone fracture
5.2.17 h'oteimuia at screening as deruonstrated by either:
r 
Uriue protein: creatiniue (uPC) ratio > 1.0 at screening (see Appadix C)
OR
r 
Urine dipstick for proteinuia > l+ $atients drscovered to have >2+
proteinuria on dipstick urinallsis at baselire should undergo a 24 hour
uriue collection and must demoustrate < lg of protein in 24 hours to be
eligible).
5,3Incluslon of Women and Mlnorltles
The National hstitute of Health (Ntr{) and NCI have stressed the importance of gender
arid minority inclusion iu clinical services and research. Feumle patients accounted for
589t, of cancer patieuts seen within The Cancer Institute of New Jersey's clinical
prcgrarus within the last year. African-Americans comprised 7%. Hispanics 89'o, and
Asiaus 3Yo of female patieuts, respectively. For all patients entering clinical tials, the
percentages were 52% women, 6% Atican-Arnedcan. 5% Hispanic. arrd 37o Asian.
No person shall, on the grouuds of age, mce. color, or natioual origin. be excluded from
participation in, or be denied the benehts of. euollment in this protocol.
5.4 Participation of Children
Patients urder the age of 18 will be excluded fi'om shrdyparticipation.
5.5 Sources or blethods of Recruitment
Patieuts r.vill be recruited through
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A Phase II Trial of Doxil , Carboplatfu a.nd Bevaciaunab in Triple Negatil'e Previously Untreafed Metastatic Breast Caocer
5,6 Study Enrollment Procedures
A copy of the institution's lRB-approved infonned conseut docrmrent and written
justification for any changes urade to the intbnned conseut for this protocol must be or
file at the Rutgers Cancet Lrstihrte of New Jersey's Office of Human Research services
(OHRS) before any participatiug instihrtion may euter patieuts. The participating
ittstitution's consent fonn must be reviewecl and approved by the OHRS and all
documents ruust be received (i.e., IRB approved documentation, IRB approved consent
fonn,).
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If a patient is registered on-shrdy but does not receive any protocol therapy, baseline data
will be collected and subrnitted accordirrg to Section 13. Dafa Collection and Records to
be Kept. No ftlilher follow-up data will be collected. The reason for uot starting protocol
therapy will be documented.
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A Phase II Trial of Doxil . C:arboplatin and Bevaciauuab in Triple Negative Frer.iorsly Untreated Metastatic Breast Cancer
6. Sfudy Parameters
The following tests and evaluatiors will be pa'forned accorditrg to the schedrde below. Baselire
(i.e., pre-study) evahrations must be perfonned no longer than 4 weeks (+/- 3 day$ prior to
therapy, turless otherwise indicated in one of the footuotes belorv the table.
1. CBC, se.ruur ctremistries and liver enzyrnes will be repeafed within 48 horus of starting fi'eatrnent thsrapy to
rccoufirm eligibility if there appeaff to be aly detedoratiou irr the patient's stafts dturug the interval between
registr ation and treatrnent.
2. Ittcludes: Electrtlyes {sodium, potassium, chloride, carbon dioxide. calcirun), BIJN, Senun Creatinine,
Glucose.
3. lncludes: Total bilinftin, SGOTISGPT. Alkaline Phosphatase. Albruuin, Total Protein
4. Women of childbearing potential must have a negative prcenancy test vedfied by senun or urite BHCG within
1 week of euollment.
5. Disease ureastuable by physical exaurilation perfonued at baseline rvithin 2 weeks (t 3 days) will be re-
evaluated after each cycle of therapy. Radiographic assessruents will be selected by the attending physician as
clinically iudicated for initial staE[ng within 4 weeks and in accordance with the criteria for tumor
measureuert assessments using RECIST criteria. Disease rueastued by imaging procedues will be repeated
after every 2 cycles ifclinically indicated and upon apparent prolpession.
6. Within 72 hours of the starl of the cycle beyond Cycle 1.
7. Perfonned at baseline. within 42 days pdor to first dose, every 3 cycles and one uronth after the last Doxil or
epirubiciu " cartoplatin. bevacizrunab reaft]ent (see Section 7.l.l.I). Echocardiograar urrry be used if IvIUGA scau
is not ar.ailable, but the sanre tost nnrst be rsed throughout the study to evaluate L\rEF.
8. For patients experiencing toxiciry. courts will be rcpeated as outlined in Section 7.4 for individual toxicity
assessments,
9. ComFleted I uronth afrer tlre last dose of Doxil or epirubicrn. carboplatin, bevaciaunab trtatment.
Version Dater 10/1 7i 1 3
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Evaluatlons
Pt'e-
Studv
Weekly
Prior to Earh
Cycle6
EntI of Treatment'
hitial llistory & Physical
x
Interim Historv & Physical with Vital Siens
x
x
Toxicity Assessnent
x"
xr,
x
ECOG Perfonnance Starus
x
x
x
Weisht
x
x
CBC. differeutial. platelets$
x'
X
x
x
Senun Chemistries'
x'
x
x
Urinalysis
x'
x"
Liver Euzlmresr
x'
x
x
EKG
x
lvlUGA Scau'
x
x'
x'
CXR
x
Bone Scan
x
x"
Head CT
x
Senun or Urile Pregrancy Testa
x
Tunor measu'enenfs'
x
x
x
Survival'
x
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A Phase II Trial of Doxil . Carboplatin ard Berraciaunab iu Triple Negative Previously Uutreated Metastatic Breast Cancer
10. Prior to each cycle monitor profeiuuia by either urine protein: crcatidne (UPC) ratio or dipstick (see Section
7.1'1.2 and Appendix C). Patients discovered to harre > 2* proteinruia on dipstick ruinalysis at baseliue
should tndergo a 24 hour tuine collection urd uust demousttate < lg of protein in 24 hotus to be eligible.
11. Patients will be followed for suvival every 6 motrtl$. Time fo pmgfession will be followed usilgimaging
scaus/hunor evaluafions every 6 months unfil disease progession is fnst documented. A telephole call iray
be made for stuvival follow+rp,
12' For bone-only disease at baseline correlative iuraging (plain filnr- CT or MRi) urust be <loue to assess disease
noted on bone scan. Docuuentafion of non-lalget (bone lesion) is required. The saure diagaostic method must
be used tluoughout the study to evaluate the lesion. A boue scan will be perfonned after evely even
uunbered cycle (Cycle 2. 4" 6 etc.).
13. The fust 6 patienfs will need to be assessed for toxicity via telephone weekly for Cycle I only.
14. Perfonned wlren the patient corrres in for their visit. The toxicity evaluation is optional in between visits and
at the discretion of the lovestigator. If an asses$uelrt is done, it may be done over the phone.
7. Treatment Plan
7.1 General Considerations
A cycle is defiued as an interval of 28 daln (delays due to holidays. weekends aud bad
weather will be permitted ancl will not be counted as a protocol violation). No investigational
ol'coruuercial agerrts or tltempies other tlran those descrjbed belolv tuay be adruinistered with
the irrtent to h'eat the patient's maligilancy. Shrdy treatmelt rvill be adrnlristered ultil
disease progtession, 2nd primary malignancy (except curatively treated nonmelanoma skin
carcer or car"cinoma in siru of the cerix), uuacceptable toxicity or rvithdrawal of consent
occurs. Patients rlay discontinue therapy at any time for any reason.
7.1.1 Drug Specilic Safety Mcnitoring Procetlures
Note: When there is a shofiage of doxil at the
patients rvill be allor.ved to rcceive treatrnent ivith
in. a conulercially available
altemative anthracycline. Treatnreut r.vould then consist
(AUC 5) and bevacizruuab (10 rr.gtg) in patients rvith.
brcast cancer.
of epinrbicirr (60 mg/m2), car"boplatin
ER. PR, HER2rea negative nietastatic
Epirubicin and carboplatin will be given on Day I of a 28 day cycle followed by
bevaciaunab on Day l. Bevacizumab will also be given ou Day l5 of the 28 day cycle.
Epinrbicin will be calculated using the patieut's acfiml u,eiglrt iu the determination of body
surface alea. fV adrninistration rvill be given over 15 to 20 mimrtes.
AII treahnent parameters, safety pararneters and requirernents will be followed as per
protocol and orrtlined iu the following sections.
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A Phase II Trial of Doxil , Carboplatin and Bevacizuruab in Triple Negatire Previously Unbeated Metastatic Breast Caocer
7.l.l.l Cardiac Safety Monitoring
Cardiac Safetv Monitorine
Baseliue left veutricular ejectiorr fraction (L\,EF) detenninations rvill be petfonned on all
patierits prior to enrollment in the trial. Patients will not be ennclled if LVEF is below
institutioml nounal lirnits.
Once on study, all patieuts will be monitored for a decrease in left venkicular ejection
fiaction (LVEF) based on the eriteria belolv.
Treahneut with DOXIL or epinrbicin should be cliscontirrued if there is cardiac dysfiurction as
indicated by:
o slanptornatic an'hyt$mia or congestive heart failure, or
r a decrease in LVEF to belorv tlte irrstitutional lorver lirnit of nonnal and at least an
absolute 5 pacentage points decrease frorn the patient's baselure L\''EF value (e.g.,
45% to 40%). or
. auy absolute decrease of 15 perceutage points or tuore froru the patieut's baseliue
value (e.g. 60% to 45%).
MUGA or ECHO (LVEF} Sctoedule for all uatients:
o Prior antlu'acycline doses exceediug 360 mg/lr2 for doxonrbiciu (includrng DOXIL) or
72A m$rf for epirubicia are not allowed.
LVEF assessment performed by MUGA scatr every 3 cycles and one month after the last
Doxil or epinrbicin, car-boplatin, bevacizrunab treatment, Echocardiogl"nl may be used if
MUGA scan is uot available, but the sanie test must be used thr"oughout the shrdy to evaluate
LVEF.
7.1.L.2 Bevacizumah
r Hpertension will be monitored through routine evaluation of blood pressur€ prior to
each bevacizumab freatnent. Optimal confrol of blood pressulE according to standard
public health guidelines is recommended for patieuts on treatment with or without
bevacizuruab.
r Proteinuria will be monitored by tuure protein:creatinine (IIPC) ratio or dipstick pnor
to each cycle.
r If patierts on [eahnent with bevacizruuab require elective major surgery it is
reconlnended that bevacizumab be held for 4-8 weeks prior to the surgical procedrue.
Patients undergoing a major sugical procedure should uot begirlrestart bevacizuruab
until 4 weeks after that procedrue (in the case of high risk procedures such as liver
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