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| 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 Phase II Trial of Doxil , Carboplatin and Bevacizumab in Triple Negative Previously Untreated Metastatic Breast Cancer
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table of contents

| 1.                                                                         | PURPOSE/SPECIFTC OBJECTIVES                    |  5   |
|----------------------------------------------------------------------------|------------------------------------------------|------|
| 2.                                                                         | BACKGROIJND AND SIGNIFICANCE..,,               | 5    |
| 3.                                                                         | PARTICIPATING INSTITTTTIONS                    |      |
| 4.                                                                         | EXPERIMENTAL DESIGN AND METHODS                | ..9  |
| 5.                                                                         | PATIENTSELECTIONCRITERIA.                      | 9    |
| 5.3 INCLUSToNoFWoIGN AND}{nonrrms                                          | 11                                             |      |
| 5.5 Soutcss onMrrnoos or RscRumvcr+r                                       | 11 l?                                          |      |
| 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                                    |      |
| version Dare: 10/17/13                                                     |                                                |      |  
| 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 50 20. PUBLICATION OF RESEARCH FINDINGS 50 5l   |
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list of abbrivi4tioiis

| 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   |
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1. putaose/specllic objectlves 1.1 primary

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.
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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.  
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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.  
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).  
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).
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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 progressionfree 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.
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21 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 (3538). There have been ilumerous repofts denronsh'ating that breast ftunorc rvill segregate iuto prognostic categories based on hierarchical cluster analysis of gene exprcssion profiling
(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 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).
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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.
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3. particlpatin g institutions 4.

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.
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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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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.
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5.2 exclusion criteria a patient

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.  
A II Trial of . Carboplatil zurd Bevaciamrab irr Triple Negative Prelio[sly U[treafed Metasmtic Breast Cancer  
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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).
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53incluslon 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.
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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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56 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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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.  
| Evaluatlons                                                                                                         | Pt'eStudv    | Weekly   | Prior to Earh   | EntI of Treatment'   |
|---------------------------------------------------------------------------------------------------------------------|----|----------|-----------------|----------------------|
| Cycle6                                                                                                              |    |          |                 |                      |
| 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  |          |                 |                      |
| 1. CBC, se.ruur ctremistries and liver enzyrnes will be repeafed within 48 horus of starting fi'eatrnent thsrapy to |    |          |                 |                      |  
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.  
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.  
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7. treatment plan 7.1 general

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.
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7.1.1 drug specilic safety mcnitoring

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.  
7.l.l.l Cardiac Safety Monitoring
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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%).
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muga or echo (lvef} sctoedule

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