Conditions: Metastatic Breast Cancer
Keywords: negative for a protein called HER2/neu negative for estrogen receptors (ER) and progesterone receptors (PR). breast cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 31
Healthy volunteers: no

Brief summary:
The purpose of this research study is to look at the effectiveness of a combination of doxil, carboplatin and bevacizumab on metastatic breast cancer. The type of breast cancer being studied is negative for a protein called HER2/neu and for estrogen receptors (ER) and progesterone receptors (PR). HER2/neu, ER and PR are part of a family of receptors found on both cancer and normal cells. This family of receptors is important for cell growth and is found in many tumor types.This study is being conducted for the following research purposes:· To find out what effects, if any, the study drug has on metastatic breast cancer. For instance, will the study drug cause the tumor(s) to shrink or stop growing?· To test the safety of the study drugs and to see what affects it has. For instance, are there any side effects? If so, what kind of side effects does the study drug cause? How severe are the side effects, and how often do they occur?· To see if the study drugs have any effect on keeping the disease from getting worse.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Doxil intervention 2: Carboplatin intervention 3: Bevacizumab
Intervention descriptions: intervention 1: Doxil 30 mg/m2 will be administered on Day 1 of each 28-day cycle. intervention 2: Carboplatin 30 mg/m2 will be administered on Day 1 of each 28-day cycle. intervention 3: Bevacizumab 10 mg/kg will be administered on Day 1 immediately following chemotherapy and alone on Day 15 of each 28-day cycle.

Protocol document:
Prot_SAP_002.pdf: 
Official Title:
A Phase llTrial of Doxil, Carboplatin and Bevacizumab in
Triple Negative Previously Untreated Metastatic Breast
Cancer
NCT number:
NCT00608972
Document Type:
Protocol #4 SAP p. 46
Date of the
Document:
tolLT lz0ls


A Phase II Trial of Doxil . Carboplatin and Bevaciannab in Triple Negative Preliorsly Urltreated Metastatic Breast Cancer
15.7 Data Monitoring and Source Document Verilication
Each site parlicipatrng in the accrual of patietts to this prctocol will be audited tbr protocol
ancl regulatory compliance, data verification atrd sotuce documettatiol.
The Cancer Institute of New Jersey staff rvill conduct r-emote monitoring on a contimral basis of
participating institutioas with rnonicoring visits occtrring as necessary. The rnonitoring visits
will focus on veri$ing data with source docuuents. Adherence to the protocol(s). including
the prompt reportfurg of sedous adverse evenls, rvill be assessed. Fiudings of all nonitoling
visits ate recorded on a ]vlonitors Reporl. i,vhich is kept in the OHRS regulatory file.
15.8 Data antl Center Audits
OHRS staff will conduct annual audits to each participating center in accordance with OHRS
Staudard Operating Procedures (SOPs). The audit guideliues are in accordance with the Data
and Safe.ty Monitoring Plan.
16. Statistical Conslderations
The "Simon's two-stage minimax design", rvith a power :0"80 and alpha level of 0.05 will be
used to rule out au uuinterestirrg response mte of 35% (assurued with the siugle ageilt, Doxil) and
to detect if the experirnental triple comtrination Ims a higher response rale of 50%. That is, if the
response rate for the triple cornbination is less thari 35Yo, then it will not be fiutirer prusued for
larger trials. If the triple cornbination's resporse mte is tnrly 50% or greater" then the desigrr rvill
have at least 80% power to detect it.
The design calls for accruing 3I patients during stage I. If 18 or more disease progression are
observed within 1 year, tiie trial will be stopped early. Other-wise the trial will continue to accrue
another 19 patients (i.e. total of 50 patients). The probability of stoppiug early at stage I is
approximately l0% if the triple courbiuation has 45olo l-year disease proglession.
To asstue cardiac safety of the conrbiuation, initially 6 patieufs r,vill be enrolled. Assessurent of
cardiac fi.mction lvill be made after 3 cycles, If one or rlore cases of CHF are obseryed, accnral
to the study will be stopped. L\rEF rvill be a prirnary endpoint as rvell. The primary LVEF
evaluatiott lvill be based ou ao absolute decrease fiom baseline of >159'0 aud /or 10% decline
fiom baseliue to below LLN at the tirne of evaluation. If fivo or lnore patients have such a
decrease in LVEF the shrdy will be stopped. If orre patient hns such a decrease, au additional
tluee patients rvill be accrred to detennine safety. If no fu*her decreases in LVEF are noted,
additional patients {total 3l during stage [) will be accmed. If more than 3 cases of CHF are
observed with the cornbination. accrual to the shrdy will be stopped. Tlils is based on a true CHF
rate of 3.5% being cousidercd acceptable and a true CHF rate af lQotb beiug uracceptably high.
All patieuts with adequate cardiac frmction at baseline (nouual LVEF and uo history of clinically
significant crudiovascular disease) who receive prctocol trcatnent rvill be included irr the prirnary
analysis of CIIF rates. (This is corisistent r,vith the cardiac analyses of ECOG 2L04).
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A phase II Trial of Doxil , carboplatin and Bevacizunab in Triple Negative Preliorrsly unseated Metastatic Breast cancer
17. Ethical aarl Regulatory Consitlerations
17.1 Study Contluct
The pI takes futl 1-esporlsibility for the ethical conduct of the study rvith highest rcgard to
protecting the riglrts and rvelfale of patients, including, but not lirnited to' adherence to the
ithical principlei laid out in the Belmout Reporl, Declaration of Helsinki aud the Patieut's
Bill of itigfrtr. This srudy is to be couducted according to local and intemational regulations,
Good Clinical h-actice guidelines and instifutional policies ald standard operating
procedures. hr order to ensure the safety and welfare of study participailts and the scientific
vatidity of the stndy, the approved protocol must be conducted as rvritten. Should changes to
the prltocol or consent become necessaly, protocol amendments will be srrbmitted, itl
writing, to the pI and local IRB for approvai prior to implementation, unless there is an
rugentleed to elimiuate an immecliate hazard to strrdy participants. In that case' notificatiort
to pt and the local IRB will be urade as soor as possible'
17.2 Institutional Review Board Approval
h.ior to initiating or making changeiio tlre protocol. the PI must obtain rvritten approval by
au IIHSIOHRP aPProved IRB.
17.3Informed Consent
Cturent FDA, OHRP. NIH. state ancl itistitutional rcgulations coDcemittg infonued consertt
rvill be followed. A wriften consent docruuent that enrbodies tlte elernetrts of infouned
consent is reqrrired $46.116. The iuvestigator shall give the patierrt adequate oppornnity'to
read it before it is sigle{, explail all asp-ects for the stutly in lay lanpJuage and answer all of
the patient,s questiois ,=g.rdiug the study. It- the patient decides to participate i} the stttdy,
lre/she will be asked to si[l the -hrfonned bonsent Document. A copy of the sigled lnfonned
Corcent Docunent will be given to the patient and this will be docttmented in the patient's
nedical record. Patients who decline io participate or withdraw froru the shrdy will be
tr eated without prejudice.
17.4 Reccrd Retentlon
The retention of accurately recorded and reh'ievable research data is necessary in order to
etrsrue scientific intepity. Research rccords should include sufficient detail to pennit
examilation for the f*pot. of replicatirrg the research, respouding to questions that ulay
result fiou unintentiotai "rlo, 
or misinterprctation. establishing authentici$ of the recotds,
and confinning the validity of the conclusiotts.
AII patients' medical recorcls and siraclorv files/research records will be rnaiutairred il a
secured location and retained turtil specified by the OHRS'
17.5 Patient ConlltleutialitY
Infor:,atio, about study paiients will be kept confidential and nauaged accordiug to the
r-equiremeuts of the Health hrsruance PorlabiliS aud Accouiltability Act of 1996 (HIPAA).
thlse regrrlations requile a sipped patient autliorization infonuing the patient of the
following:
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A phase tr Trial of Doxil , carboplatin aad Bevacizruaab iu Triple Negative Preliously Unhealed Metasratic Breast cancer
. The protected health information (PHI) that witl be collected fr'om patient.
. Who will have access to that intbnuatiou and rvhy.
. Who will trse or disclose that itfomration'
. The rights of a research patient to revoke theil authorization for use of their PHI-
In the event that a patient revokes authodzation to coilect or use PHI" the investigator, by
regulatiol, retains the abil$ to use alt infonnatiol collected prior to the revocation of patient
arithorization. For patientr ttrut have revoked authorizatiou to collect or use PHI" attempts
should be made to obtain per:nission to collect at least vital staftrs (i-e. that the patient is
alive) at the e3d of their sch-eduled study periocl. To eusru'e colfidentiality is maiutained at all
tirnes. CRFs will uot identify any patient by Dame. A uniqrre shrdy identification mrnrber will
be recorded o1 the CRI aud all records n itt U. sectued in a locked location. No clinical
information will be released without written permlssiou of the patient, except as necessary for
monitorilg by tire IRB, FDA, OHRP and Genentech, Inc. and the Rutgers Cancer Institute of
Nerv Jersey.
17.6 Conflict of fnterest
41l Rutgers University faculty ard other ernployees who. as investigators on behalf of the
University. lvho applyfor or receive flincls tluough a grant. subgrant, contract, subcontract, or
cooperative ugt".*;t for auy tesealch, eclucatioual or sewice puryose and investigators
*oi.kiog as subgrantees. contractors or subcouhactors to or collaborators with the University
on ploj"ects fiuied or proposed for frurding ruust disc.lose any real or appareut conflict of
inteiesi ancl abide by t1" Conflict of Interest Policy irttp://policies.rutgers.edtr/ as it relates to
coadrtcting clinical resear-ch,
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A phase JI Tri6l of Doxil , carboplatin and Bevaciauuab in Triple Negative Prer{ously untrealed Metastatic Breast caucer
18. Human Subiects
18.1 Patient Population
Women with previously rurtreated ruetastatic breast carcer, ER/PRI{ER2/nerr negative.
18.2 Potential Risks
All care will be takel to minirnize side effect, but they can be turpredictable in uahue ald
severity. Risks are outlined in Section 12.
18.3 Consent Proeedures
Infonned consent must be obtained prior to cornmencilg any reseatch procedures. The PI
slall seek such conserrt only under such citcurustances that provide tire prospective patieat
opportunity to consider whether or uot to participate and that minimizes the possibility of
coircion or rmdue influence. The inforuation given to the patierrt, or the representative, shall
be i1 a language urrclerstandable to the patient or lepresentative. The informed consent
docuueut rray uot ilclude any exculpatory laugrrage tluough which the patient or
representative is made to waive any of the patient's legal rights or releases, ot appears to
,"i"uu. the ilvestigafor, fhe sponsor or the instinrtion frorn liability for:regligence.
18.4 ?otential Beuelits
potential benefits may be reduction in the size of firuor, improved ttuuor response, stabilify
i1 size of tu1or, a louger period ol progression fiee suryival anrUor improvement ia
synpfouts related to their disease.
18.5 Risk-Benefit Ratio
The potential benefit that may result frorn this shrdy balances the potential risks to the
patierits. Resllts of previous kials suggests that these dmgs are active against breast cancer.
This protocol may or *uy not be helpflil to a specific patient, but the results may help the
Investigators learn abo* the adrmnistration and effectiveness of doxil or epinrbicin,
carboplatin antl bevacizrunab iu breast cailcer and may aid in the treatmenl of other patients'
This iesearch treatnrent is not curative. but rnay offer fenrporaty control of the <lisease'
Beneht can't be promisecl nor can the chance of benefit be acctuately pr-edicted- Literature
presentations on iecelt studies using these dnrgs in breast cancer patients do not suggest afl
wmcceptable dsk-benefi t ratio.
I
No persou shall, on the gorurds of age, race. color. or national origin, be excluded froru
participation in, or be denied the benefrts of, enrollment in this protocol.
Version Date: 10ll 7/1 3
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18.6 Gender antl Minorities
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A Phase II Trial ofDoxil . Cartoplarin aad Bevaciauuab in Triple Negative Preliously Untreafed l\{etastatic Breast Cancer
19. EconomiclFinanclal Consltlerations
Patients audlor their insurarrce caniers will be expected to pay for all costs of therapy,
illolitodng, and follorv-up. Bevacizruuab will be provided free of charge by Geuentech, hrc.
respectively.
20. Publication of Research Findings
The policies and procedures of the
nmrner following the conclusion. The PI, and all co-
authors prior to subruission or use: rnust review any abstlact or mauuscript.
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A phase II Trial of Doxil . carboplarin and Ber,acizuruab ill Triple Negative Previo[sly urtreated Metastatic Breast cancer
References
L Hortobagyi, G. N., Singletary, S. 8., and Sh'out, E. A. Treatmeil of Locally Advanced and
krflanulatory Breast Caucer. hr: J. R. Harris, M. E. Lippurau, M. Morow, and C. K. Osbome
(eds,), Diseases of the Breast, 2nd edition, pp. 645-660. Philadelphia: Lippincott, Williaurs
and Wilkius.2000.
2. Br.em SS. Gullino PM. Medina D: Angiogenesis: a rrrarker for teoplastic transfonnation of
luarnfllary papillary hyperplasia. Scie.nce 1 97 7 ; I 9 5 : 8 80-2.
3. Jensen fiM,bh* I,-ieVault MR. eI ai. Angiogenesis iuduced by "normal" hutnar breast
tissue: a probable marker for precancer. Science 1982; 218:293-5.
4. Kurebayashi J, Mcleskey SW, Johnson Ir,ID, et a/. Quantitative demonsfiation of spontaneous
ruetastasis by MCF-7 huuan brcast caucer cells cotransfected with fibroblast growth factor 4
and LacZ. Cancer Res 1993; -53:2178-87-
5. Mcleskey SW, Zfuang L, Kharbanda S, er a/. Fibroblast gtorvth factor overexpressi[g breast
carciloma cells as *o,l"lt of angiogeuesis and metastasis. Breast Cancer Res Treat 1996;
39:103-17.
6. Mcpskey SW, Tobias CA, Yezza PR, et a/. Tuuor growth of FGF or VEGF transfected
MCF-7 breast c.arcinoma cells conrlates with density of specific microvessels independent of
the trausfected argiogeuic factor. Am J Pathol 1998; 153:1993-?006.
7. ZhaIlgHT, Craft P, icott PA. et ol. Enhalceurent of ttunor growtir and vascular density by
transfiction of vasculal endothelial cell growth factor into MCF-7 lnrman breast carcinoura
cells. J Natl Cancer Inst 1995; 87:213-9.
8. Nakajina M" Welch DR, Wym Dlrit. et a/. Serum and plasura M(r) 92.000 progelatinase levels
*orr"lut" with spontarleous rnetastasis of rat I3762NF mammary adenocarcinoura. Cancer Res
1993; 53:5802-7.
9. Gitrnciuglio D, Culfy M, Fassina G. e.r ol. Invasive phenotype of MCFlOA cells
orr"r.*pritring c-Ha+as and c-er"bB-2 ottcogetres. Iut J Cattcer 1995: 63:815-822'
10. Weinstat-Saslow DL, Zabrerretzky VS, Var*loutte K, et al. Transfectiou of tluornbospondiu
I compleruentary DNA ilto a huuan breast carcinoma cell line reduces primary truuor
growth, metastatic potential, and angiogenesis. Caucer Res 1994; 54:6504-11-
I l.-Warrg M, Liu Yf, Creene J, er al. krhibition of tumor gowth and metastasis of hunran lxeast
cancer cells tmnsfected with tissue inhibitor of metalloprotefurase 4. Oncogene 1997: 14:7767-
74.
12. Liotta I-A" Steeg PS, Stetler-Stevenson WG: Ca[cer mefastasis and angiogenesis: an
imbalance of positive and negative regrrlation. Cell 1991: 64:327-16.
13. Guinebretiere IM, Le Monique G. Gavoille A. er al. Algiogenesis aud risk of breast cancer in
wolnen with fibrocystic disease fietter; commeut]. J Natl Cancer Inst 1994, 86'635-6.
14. Guidi AJ, Fischer L. Hanis JR, e/ a/. Micrcvessel deusity and distribution in ductal
carcinoma in situ of the breast. J Natl Cancer Inst 1994; 86:614-9.
15. Engels K, Fox SB, Whitehotrse RM, er a/. Disti[ct angiogenic pattems ale associated with
high-gpde in situ ductal carcinomas of the breast. J Pathol 19971 l8l:207-12-
16. Gtridi AJ, Schnitt SJ. Fischer L, et al. Vascular penneability factor (vascular eudothelial
growth factor) expressiou and angiogelesis in patients lvith ductal carcilrotua in situ of the
breast. Cancer 1997; 80:1945--53.
Version Date: 10/17113
-
-51 -


A phase II Trial of Doxil , Carboplatin and Bevaciarnab in Triple Negatil'e Prelior$ly Untrealed Metastatic Breast Caocer
17. Folkrnan J: What is the evidence that ftimors are angiogeliesis dependeilt? J Natl Cancer Inst
1990;82:4-6.
18. Ferara N, Davis-Snryth T: The biology of vascular endothelial growth factor- Eudocrinol
Rev 1997.
19. Relf M, LeJeune S, Scott PA, ef ai. Expression of the angiogenic factors vasculal endothelial
cell grorvth factor. acidic ancl basic fibroblast gtorvth factor, fltutor gfowth factor beta-l,
plateletderived endothelial cell growth tactor, placenta gtowth factor, and pleiotrophin in
ir,rn u, primary breast cancer and its relation to angiogenesis. Cancer Res 1997; 57:963-9.
20. Gasparini G. Toi M, Giou M, et a/. Progrostic significance of vascular endothelial porvth
factor protein in node-negative breast carcinorua. J Natl Calcer Inst 1997; 89:139-47.
21. Linderholm B, Tavelirr B" Grankvist K, el al. Vascular endothelial growth factor is of high
progpostic value in uode- negative breast carciuoma. J Clin Oncol 1998; 16:3121-8-
ZZ. toi M, Kondo S, Sruuki H, et ol. Quarrtitative aualysis of vascular endothelial growtlt factor
in prinrary breast cancer. Cancer 1996; 7 7 :1 10 l -6.
23. Eppegberger U, Kuerrg W. Schlaeppi IM, et al. Markers of tumor angiogenesis and
proteolysis independently defirre high- and low-risk subsets of node-negative breast cancer
patients, J Clin Oncol 1998; l6:3129-36-
24. pham CD, Roberts TP, vau Bnlggen N, et al. Magnetic lesorance imaging detects
suppression of ttrnror vascular penneability after adrninistration of attibody to vascular
endothelial growth factor. Cascer Lrvest 1998; I6:225-30'
2-5. Borgshon i, Gold DP, Hillan KJ, et al. hnpo(ance of VEGF for breast cancer angiogenesis
in v]vo: inrplications from inhavital microscopy of corubination treaturents with an anti-
VEGF treuftalizirg ruouocloual antibody aud doxonrbiciu. Anticalcer Res 1999'.19.4203-14'
26. Fresta LG, Chen H, o'Corrror SJ, er a/- Humanization of atr anti-vasclilar endothelial growth
factor moloclonal autibocly for the therapy of solid tunors aud other disorders. Caflcer Res
1997;57:4593-9.
27. Sclneider, B.P., Miller, K.D., fugiogenesis of Breast Cancer. J Clin Oucol- 2005 Mar
10:23(8):1782-90.
28. Miller. K.D., Wang, M., Gralow, J. Dickler. M'. Cobleigh' M.. Perez. E', Sheukier, T',
Davidson. N. A laudomized Phase m rial of paclitaxel versus paclitaxel plus bevacizumab
as first-li1e therapy for locally recurent or metastatic breast carcer. Proceedings of ASCO,
2005
29. Perau CM, Sorlie T, Eisen MB, et al: Molecular portlaits of luunan breast tumorus. Nature
406:747-52,2000
30. Sorlie T: Molecglar portaits of breast cancer: ftrmour subtypes as clisti[ct disease entities.
Eur J Caucer 40:2667-75.2004
31. Sorlie T. perou CM. Tibshiraui R. et al: Gene expression pattems of breast calcinomas
distingrrish ftulor subclasses rvitli cliuical implicatiorrs. Proc Natl Acad Sci U S A 98:10869-
74.2041
32. Brenton JD. Carey LA, Ahmed AA, et al: Molecular classification arrd moleculal forecastiflg
of breast ca&cer: ready for clinical application? J Clin Oncol23:7350-60, 2005
33. Rouzier R, Pelou -M, Syr*oos WF, et al: Breast cancer uolecular subtypes respond
differeutly to preoperative chemotherapy. Clin Caucer Res l1:5678-85, 2005
Version Date: 10117/13
-
-<)-


A phase II Trial oiDoril . Carboplatin and Bevacianruab iu Triple Negative Previously Uflt'eated Metastatic Breast caocer
34. Sotiriou C, Neo Sy, Mcshane LM. et al: Breast cancer classification atd prognosis based on
gene exptession proftles frorn a populatiol-based study. Proc Natl Acad Sci U S A
100: I0393-8, 2003
35. Charafe-Jauffiet E, Ginestier C, lr4onville F, et al: How to best classiff breast cancet:
conventional and uovel classifications (review). hrt J Oncol2T:1307-13, 2005
36. Clrarafe-Jauffret E. Ginesder C, Monville F, ef aI: Gene expression profiling of breast cell
lines identifres potential new basal ruarkers- Oncogene, 2005
37. Jacquemier J. Gilestier C, Rougemont J. et al: Protein expression profiling identifies
subclasses of breast cancer aud predicts prognosis. Cancer Res 65:767-79,2A05
3g. Jacquemia-J, Padovani L, Rabayrol L, e{ al: Typical medullary breast carci[omas have a
basailuryoepitlrelial pirenotype. .I Pathol 207 : 2 60 -8' 2005
39. Nielsen TO, Hsu fd, fensen K, et al: Imrnunohistochenical and clinical characterizatiou of
the basal-like sutrtype of invasive breast carcitoura. Clirr Cancer Res 10:5367-74,2004
40. Sorlie T, Tibshirani R, Palker J, et al: Repeated obselation of breast hunor subtpes in
indepeuclent geue expression data sets. Proc Natl Acad Sci U S A 100:8418-23. 2003
41. Weigelt B, Hu Z,ke X, et al: N.Iolecular portraits and 7O-gene proguosis signattue arc
preseived tluoughout the metastatic process of breast cancer. Cancer Res 65:9i5-5-8, 2005
42. 
-Brelton n. eliaricio SA, Caldas C. Molecular profiling of breast carcer: porlraits but not
physiognomy. Bleast Cancer Res 3:77-80, 2001
+1. ir,latosi, O,rilott R, Alvarenga M. et al: p63, cytokeratur 5, and P-cadherin: tluee nrolecular
markers to distinguish basalphelofype ir breast catcinomas. Virchows Arcb 447:688-94.
2005
44. Romoud EH, perez EA, Bryant J, et al: Trastuzumab plus adjuvant cheurotherapy for
operable HER2-positive breast cancer. N Eng! J Med 353:1673-84, 2005
45. Tumer N, Tutt A. Ashworlh A: Halhiailrs of 'BRCfuiess' itt sporadic cancers- Nat Rev
Cancer 4:814-9. 2004
46. Tumer N, Tutt A. Ashworth A: Targeting the DNA repair defect of BRCA hu}ours. Cun'
Opin Phanlacol 5: 388-93, 2005
47. Keluredy R, Quinn J, Mullan P, Johnston P, Harhin D: The Role of BRCAI in the cellular
response to chemotherapy. JNCI, Vol 96:1659-1668,2004.
48. Flrero J., Weber 8., Lepille D, Orfeuvre H, et al: Carboplatin and pegylated liposomal
doxonrbicin ip patielts ,"ith u.tuonced ovatian cancer in late(>6 months) relapse: Survival
results of a GINECO phase tr trial. Proceediugs of ASCO,2O04:5022.
49. du Bois a, Bur.ges u, M.i.r W, et al: Pegylated liposornal doxonrbicin and carboplatin iu
advanced gmecologic tumors: a prospective phase UII sttldy of the Artreitsgerneinschaft
Gynaekologische d:kologie Sftrdiengrirpp. Ovariallmrzinom (AGO-OVAR). fuin Oncol.,
2005.
50. t e L, Swwene(ou K, Elit L, et al: Plrase II rnutlicerrter opeu-label study of carboplatin and
pelylated liposomal doxonrbicin in uterine axl ceryical nraligrrancies. Int J. Gyrecol Cancer
15: 799-806, 2005.
-51. D'Adarno, D, Andercon S, Albrifton K, el al: Phase II study of doxonrbicin and bevacizruuab
for patients with metastatic soft-tissue sarcoluas. J Clin Oncol 23 1135-7142.2045 -
SZ. ftaaaaa P.A., Slorbitz K.M.: Colrbination of bevacizumab (A) and pegylatedJiposomal
doxorubicin (PLD) (PLD-A) irr sarcoma (SAR) Jour:ral of Clinical Oncology, ASCO Arurual
Meefing ProceediDgs, vol24, No. 18s (Jtne 20 Supplement), 2006:9556.
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A phase II Trial of Doxil , Carboplntin and Bevacianurab in Triple Negative Pret'iouslyUrltreated Metastatic Breast Cancer
53. O'Brien M, Wigler N. Iubar M, et al: Reduced cardiotoxicity and compamble effrc.acy in a
phase Itr trial of pegylated liposorual doxonrbicin HCI versus couveutional doxonrbicin for
frrstline treahnerrt of ruetastatic breast cancer. Aurals of Oncology 15 44A-M9, 2004
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A Phase II Trial of Doxil . Carboplath zurd Ber.acianflrab in Triple Negative Previo[sly Utlteated l{etastatic Breast Cancer
Appendix A
Performance Status Criteria
f,COG Performance Status Scale
Karnofsky Performance Scale
Grade
Desuiptiorrs
Percent
Descriptiol
0
Nonual activity. Fully active. able to
carry on all pre-di*ase perfotnrance
uithout restrictiorr
100
Nomral. uo courplaiuts, no evidence of
disease.
90
Able lo carry oD nonnal actil'ity: minor
silns or symptolrs of disease.
1
Synrptorus, but arubulatory. Reslricted
in physically steuuors activity, but
ambulatory and able to cany ottt work
of a light or salerrtary natue (e.g..
light houseu,or*. office uork).
80
Nornal activirywith effort some sigrx or
syrup{otus of disease.
70
Cales for self, turable to carry ol nornral
activity or to do active wolk.
2
In bed <507o of the tiure. Alrbulatory
and capable of all self+are, Intt urable
to cany out any r,r'ork actirities. Up
and about nrore than 50% ofuaking
hours.
60
Requires occasional assistauce, but is able
to care for urosl of hiy'lrer needs.
50
Rsquires cousiderable assistalce and
&eouert medical care.
3
lnbed >500/o of the tilre. Capable of
only limited self-care. cotfiaed to bed
or clnir tnore than 50?6 of waking
hours.
40
Disabted, tequircs special care and
assistagce.
_t0
Ser,erely disabled. hospitalization
ildicated. Death uot irtmineut.
4
100% bedddden. Courpletely
disabled. Carurot ciury on any self-
care. Totally confiled to bed or chair.
20
Very sick. hospitalization indicated
Death not inurriuent.
l0
Moribuud, fatat processes progtre$smg
rapidly.
5
Dead.
0
Dead.
Version Date: 1Oil 7i1-l
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A phase II Trial of Doril , Carboplatin zurd Bevacizruuab iu Triple Negatir,'e Previo[slyUntreared Metastatic Breast cancer
Appendix B
Soruc.: Cdt"daCommittee, Nerv Yort Heaf Association, Inc. Diseases of the heafi
and blood vessels. Nomenclahue and cr:iteria for diagnosis. 9e ed. Boston, Little.
Brown and Co. 1,994:253-6.
New York Heart Association Crlteria
Class
I 
No lirlitation: Ordinary physical activity does not cause urdue fatigue,
dyspnea, palpitation or augiual pait.
tr 
Slight lirnitation of physical activity: Such patients are comfortable at rest.
Ordiuaryphysical activity results in fatig[e, palpitatious, dyspnea, or
anghal pain.
1g 
Marked limitatiou of physical activity: Although patieuts are coarforlable
at rest, less that ordirrary physical activity will lead to syurptotus.
ry 
Inability to carry orr physical activity without discoruforl: Syruptoms of
cardiac irrsufficieucy or of anginal syndlorne may be present even at rest.
With any physical activiry, increased discomforl is experi
Version Date: 10117113
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A Phase II Trial of Doxil , Carboplatin ard Ber,aciaunab in Triple Negative Previo[sly Unreated Metastatic Breast Cancer
Appendix C
Procedure for Obtalnlng a Urlne Proteln / Creatinlne Ratlo (UPC)
I) Obtain at least 4 ml of a random urine sample (does not have to be a 24 horr urine)
2) Detenuine proteiu concentration (tng/dl)
3) Detennine creatinine concenhation (mg/dl)
4) Divide #Zby #3 above: urine protein / crcatiniae mtio:
protein conceatation (mg /dL) lcreatiline concentration (mg ldl-)
TIre UPC direct$ conelates with the aruount of protein excreted in tlre urine per 74 hrs (i.e. a
UPC of I should be equivalent to lg proteiu in a 24lu ruine collectiou)
Protein aud creatinine concentrations should be available on standard reports of urinalyses, not
dipsticks. If protein and creatinine coucenhations arc uot routinely reported at an lustitutiot,
their measruemsnts and reports will ueed to be rcquested.
Venion Date: 10117/13
-
-57-

Prot_001.pdf: 
Official Title:
A Phase ll Trial of Doxil, CarUo
Triple Negative Previousry Untreated Metastatic Breast
Cancer
NCT number:
NCT00608972


A Phase rI Trial oi'Doxil ' calboplarifl ald Berraciauuab in Triple Negatire previo[sly unbeated Nletasratic Breast cancer
resection, tltoracotomy, or neuloilugery, it is reconuneded that c,hemothuapy be
restarted no earlier than 6 weeks and bevaciztunab no earlier thau g weeks after
nugery).
7.2 Dose Crlculation
Doses of Doxil or epimbicin will be calculated usiug the patient's achml weight i1 the
deternri$ation of body stuface area. A vmiance of S"/o'of the calculated total dose will be
allowed.
BSA(m2;: 
@nr 
w
\/f 
or\1ffi
Doses of carboplatin will be calculated based on seruln creatiuine using the nodified Calvert
formula:
Total dose 0ng): Target AUC (mg/rnl x rnil) x [Creatinine Clearance (nrl/min) + 25]
Creatinine clealance can either be measured or estimated usi[g the Cockroft-Gault fomrula,
as follows:
creatinine clearauce (ruumin): (.140 - age in liears) x ()veight iu ke) x O.gj
/2 x senun crcatinine (rug/dl,)
7.3 Treatment Atlminlstration
Ca$oplatin (AUC 5) and either Doxil 30 rnglm2 or epirubicin 60 mg/mz will be admilistered
ou Day I of each 28-day cycle. Bevacizumab 10 mg,kg wil bJadministered on Day I
immediately fiollowing chemotherapy and alone on Day 15 of each 2g-day cycle.
7.3.1 Carboplatin
Carboplati[ at target AUC : 5 mglnfl/min will be administered by [V infusion over
30 - 60 urinutes.
7.3.2 Doxil
To mirfmize the risk of infusiou-related reactions, the fust infusion of Doxil should
be administered over g0 rninutes. as follows:
r 
l0 mL over {irst l0 minutes
o 
20 mLovernext l0minutes
t 
167 mlJnun urtil completiou of the infrrsiou.
If no infrrsion-related reactiom are noted with the initial iufrrsion, subsequent
infisions will occru at a rate of I rng/minufe,
\:ersion Date: 10ll 7i13
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A Phase rI Trial ofDoxil . carboplatin and Bevacianuab in Triple Negative prer,iously Untreated Iuetasratic Breast cancer
7.3.3 Bevacizumab
Bevacizumab l0 mg&g will be adnrinistered by IV nftrsion. furaplylaxis
precautions should be obseruecl druing shrdy dnrg admirrishation.
The initial dose will be delivered over 90 +15 minutes. ff the fu.st infusion is
tolerated without infrrsion-associated adverse events (fever aud/or chills), t5e secoucl
infiuion may be delivered over 60 *10 minutes. If the 60 minute infiuion is well
tolerated all strbsequent ilfusious nray be <lelivered over 30 tlO nimrtes.
If a patient experieuces an inftision-associated adverse event. she may be
prernedicated for the next shrdy dnrg ilfrrsion, howeyer, fhe infusion tirue nray not be
decreased for the subsequent infusion. If the next furfusiou is well foleratecl with
prernedication, lhe subsequent infusion time may then be decreased by 30 tlg
minutes' to a minimrun iufusion tirne of 30 minutes, as long as the patient continues
to be premedicated. If a prernedicated patient experiences an itfusion-associated
adverce event with the 60 urinufe infusion, all subsequent doses should be given over
90 tl5 tninutes. Sfunilarly, if a premedicated patient experiences an iufusion-
associated adverse event with tire ,10 minute infirsion, all subsiquent doses should be
given over 60 +10 milutes.
7.3.4 Epirubicin
In the event of a shoftage of doxil, patiants will be allowed to receive epimbicin.
Epinrbicin will be given byrv adrninistratiu over l5 to 20 milutes.
7..1 Dose ilIodilications
Chernotherapy dose adjushuents are to be made according to the system showilg the greatest
{*gt : of toxicity. Toxicities/adverse events will be gradecl using the NCI Comrnon
Termiuology Criteria for Adverse Events. Version 3.0. Patients ore allowed a ruaxiuurn of 2
dose reductiorx.
If toxicity or adverse events cause one study dnrg to be hekl. all shrdy drug doses will be hel{
trntil criteda is met to resunte dosing.
If doxil or epinrbicil if used in place of doxil or carboplatin is discontinued the patient will
be takea off study. If bevaciaxuab is discontinued the patient may coutinue to receive doxil
or epinrbicin and calboplatin.
Chemotherapy will be held for a uraximun of 3 weeks for toxicity or adverse events. ffafter
3 .weeks ro recovety is seen. sttrdy dnrgs will be penuauently discontinued alrd the patiegt
will be renoved frorn fhe study.
Treahnent with DOXIL or epinrbicin should be discontinued if there is cardiac dlrfrrnction as
indicated by:
\iersion Date: 10ll7i 1-l
-
-17-


A Phase II Trial of Doxil , carboplatirl and Bevaciaunab in Triple Negaiir.e previously unheated N,tetastatic Breast cancer
synptomatic arhythruia ol.congestive heart faihue, or
a decrease in LVEF to belorv the institutional lower limit of nonnal and at least an
1!rylute 5 perceufage poitrts decrcase from the patient's baseline LVEF uufo. ir.g.,
45Yo to 4oo/o), or
any absolute decrease of 15 percentage points or rlore fi"om the patient's baselile
value (e.g. 60% to 45%).
Dose reduction is plaDned in case of severe hematological and/or non-hematological
toxicities as follows:
carboplatiu: from AUC 5 mg/rnl/urin to AUC of 4 mg/mlJmin
Doxil: fi'om 30 rngrm2 to 24 11Ilg/n2
Epintbicin if used in place of doxil witl be reduced by 2}o/o from 60 mg/m2 to 4g ruglm2.
No additional dose tedttctions may be given. ft'toxicity occurs that wopld iudicate a fi,ther
dose reductiou is ueeded, the patient will be reruoved fi'orn the sfurdy. Doses, rvhich have
beeu reduced for toxicity, must ttot be re-escalated r,vith the exceptiori of liver fi.mctio* tests
that improve within tanges given.
Version Date: t0/17/13
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-18-


A Phase II Trial of Doxil , Carboplatin and Bevacianuab in Triple Negative Predorsly Untreated lr{etastatic Breast Caucer
IIEI\{ATOLOGICAL TOXIC;ITY
^{\C
cellslnunr
MODIFICATION
> 1.000
Resrune ffeatment rvith no dose reducfion.
< 1000
For AI.IC < 1,000/rrunr delay adrtiristration
urltil ANC > 1.000.
For the frst episode, resume treahnent at full
dose with peg-filgrastiur support Lritiated on
Day 2. All remaining cycles rnay be given with
peg-filgrastiru at Investigator's discretion.
For a second episode. if ANC takes S 3 weeks
to rec.over to > 1.000 with peg-filgr-astim
slrppoff. reduce carboplatin to AUC of 4
rng/u[/mfu and doxil ro 24 nrg/nf or epirubicin
to 48 mg/r#.
If after a 3-lveek delay ANC has not recovered
the patient will be taken offsrudy.
PLATELETS
cells/n:ur3
I\IODIFICATION
> 75,000 -
Restuue treatrneilt with no dose reduction.
<75,000
If PLT count \,vas > 25.0001uuu3 and i'ecovers to
75,000/mm3 rvithiu 3 weeks. resutr]e carboplalin
ald doxil or epinrbicin administration at full
dose.
If platelet count was S 25.0@/nuu3 and
recovers to 75,000/mrlr within 3 weeks. reduce
car-boplatin to AUC of 4 rng/trl-./min and
maintain the doxil or epin6icin dose.
Cheurotherapy will be held for a maxirnrun of 3
weeks. If after 3 weeks, no recovery above
75,000/nuni is seen t5e shrdy dnrgs will be
permauently discontinued and the patient will
be taken offstudy.
\rersion Date: l0/17i1 3
-
-19-


A Phase rI Trial of Doril . c:arboplatin and Bevaciauuab in Triple Negatire prer{ously unteated }r{etastatic Breasr ca,cer
7.{.1 Carboplatin
Febrile Neutr.openia
Febrile neuhoperia shall be defined as oral or tyrnpanic fever of > 3g.5 o C gr 101.3 o r jF in
the presence of neuh'openia (where ueutropenia is defined as ANC < fooOirrurfl. e
therapetltic intervention should proceed inunediately following the diagnosis of febr:ile
neutropeuia. Therapeutic iuterventiors car be as p*i the institition's griia"m"r, or 111ay
include:
o hospital adruission
o prc-antibiotic evaluation
o cBC with differential and blood culfiue sho*ld be perfon,ecl
r start of an empirical antibiotic fherapy
In case of febrile neufunpenia, blood counts must be done every 2 days until recovery of ANC
) l'000/nun3 or oml temperature < 38.5 oC. This must be documeuted in the specific adverse
eveut sectiou of the CRFs,
For the first episode, lesune treatrnent at frrll close rvith peg-filgrastim support. If despite
peSfilgastilr support, a second episode occurs close recluce carboplatin to + eUC and doxil
to 24 rng.r#. If a third episode or.*', the patient will tre taken off-shrdy.
hfection \Hith (or Without) Neutropenia
For severc (Grade 3) or life-tlu'eatening (Grade 4) infectiorr during chemotherapy, with or
without neutropenia, prophylactic G-CSF and prophylactic antibioiics will be aided to all
remaining cycles. Levofloxacin is recommendecl at 500 mg oral dose daily for l0 daya
starting on Day 5 of each cycle for renmining chemotherapy-cycles. If levofloxacin is not
available or not tolerated, another oral antibiotic must be usert. The choice of antibiotic is at
the discretion of the Investigator. G-CSF will be added to all subsequent chemotherapy
cycles as per ASCO guirlelines-
2nd Febrile Neutropenia and 2nd Infection Event
h the case of a second febrile neuh'openia or infection evert, patient will coptisue rvith the
prophylactic G-CSF for all subsequant cycles. Irr acldition, all cheurotherapeutic drug doses
will be reduced for all renmiuittg cycles. hr the case of a 3rd event, there ivill be no f*rther
dose reduction. The patient will stop carboplatiu and be removed frorn the study.
Anemla
In case of Grade 2 decrease in hernoglobin, treaturent with blood hansfrsion or erytluopoietin
sho*ld be given- The use of prohylactic erythropoietin for Grade ( 2 anemia is discoruaged.
The choice of the type of eryttropoietin used (loug actiug or regular) is at the Investigatir's
discretion. ln case ol',rGrade 3 or 4 deerease in hemoglobin. doses shoulcl be reduced as
follows: carboplatin reduced from an AUC of 5 mg/n:I7min to a1 AUC of 4 prg/rnUr'in,
Maintain the doxil or epinrbicin dose.
Version Datet l0/17/t.]
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A Phase II Trial of Doxil , Ca$oplatin zurd Bevaciztutxb in Triple Negative Previously Untreated Metastatic Breast cancer
Nausea and Vomltlng
Alliemetic prophylaxis is mandatory for all patients. Selection of autienretics is at the
discretion of the Lrvestigator. Acute episodes o],rr,,r", aud vomitilg sho*lcl be coutrolled
with adequate antiernetics. In case of Grade 4 voruitiug that persisis clespite antiemetics,
patient will discontinue carboplatin ancl tre rcnroved fronr ihe stucly.
Stomatitis
In case of Grade 4 stomatitis (au#or esophagitis) the patient will discontinue carboplati* and
be removed from the shldy.
Peripheral Neuropathy
If the patient experiences peripheral neuopathy of Grade 2 the follorvirrg dose modilicatious
should be petfonned: Delay carboplatin treaturent by a maximum of trvo weeks. As soou as
patient recovel's. treatment should continue r,vith tiie following dose recomruendations:
o If patieut recovers to Grade I toxicity, maiutairi the carboplatin and doxil or
epirubicin doses.
o If Grade 2 persists for ) 2 lveeks. patient will cliscontinue carboplatin and be
removed frour the study.
In case of a second episode, maiutain the carboplatiri dose. If the patient experiences another
episode, rto fiuther dose rcductiott is plarured and the patient will discoutinue carboplatin and
be removed froru the study.
Cutaneous Reactions
r For Grade 4: Patient will be taken ofl'-shrdy.
7.4.2 Doxll
Patieuts should be carefully ruonitored for toxicity. Adverse events, such as F{FS,
hanatologic toxicities, and stornatitis may be nanaged by dose delays and adjustment.
Following the first appe:uance of a Grade 2 or higher adverse event. the dosing should be
adrxted or delayed as described in the following tables. Once the dose has been recluced, it
should not be increased at a later tirne.
Version Date: l0/17/13
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- 1l -


A Phase II Trial of Doxil , Carboplatin and Berraciaunab in Triple Negative Preliorsly Untreated Metastatic Breast Cancer
HAND rOOT SYNDROME HrS)
Toxicity Gratle
Dose Adjustment
I
(mild erytheura,
swellilg, or
desquanration not
inteder*ng with daily
activities)
Redose unless patient has experienced prel.ious Grade 3 or 4
IIFS. Ifso. delay up to 2 rveeks and decrease doxil dose by 2oolo.
2
(erythenm"
desquanratiorr, or
swelling intefering
rvith. but not
precludiug normal
physical activities:
sumll blisters or
rrlcemtions less thau 2
cm in diameter.)
Delay dosing up fo 2 rveeks or until resolverl to Grade 0-I. If
after 2 weeks there is no resolution, patiert ivitl be rernoved fi'our
the sftldy. If resolved to Grade 0-l withh 2 weeks. and there are
no pdor Grade 3-4 HFS, coutinue doxil treatmert at previous
dose and retum lo original dose interval. If patient experienced
previous Grade 34 toricity. continue tleatnlent .,vith a 2096 dose
reductiou of doxil.
3
(blistering ulcemtion,
or swelling interfe.rir:g
wift walking or normal
daily activities: cannot
rveal re gt*al clothine)
Delay dosing up to 2 weeks or until resolved to Grade 0-I.
Decrease doxil dose by 20%. If afrer ? weeks there is no
resolution. Doxilo should be discontinued.
4
(diffuse or local
process causing
infectiorx
complications. or a bed
ridden state or
hospitalization)
Delay dosing up to 2 weeks or until resolved to Grade 0-I.
Decrease dose by ZAVo andrehur to original dose interval. If after
2 rveeks there is no resohrfion, Doxil@ should be rliscontitued-
Yersion Dale: l0/l 7/l l
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-)', -


A Phase tr Trial ofDoxil , Carboplatin and Bevaciauuab iu Triple Negative Freliorsly Untreated Metastatic Breasi cancer
STOMATITIS
Toxicity Grade
Dose Adiustment
I
(painless ulcers,
erythenra, or urild
soreness)
Redose uiless patient hes exper.ieuced prerdous Gradi 3 or.4
toxicity. If so. delay up to 2 weeli$ aud decrease Doxiledose by
ZOYo. Mairtain the Calboplatin dose.
(pahful elythema,
ederua, or ulcers, but
can eat)
Delay tlosing up to 2 weeks or.unfil resolvetl to Gr.ade 0-1. If
after 2 weeks therc is no resolutiorl patient il.ill be reruoved fi.om
the snrdy. If rcsolved to Grade 0-l within 2 weeks, and there was
no prior Grade 3-4 stomatitis. continue tr€atment at previous
dose. If patiurt experience previous Grade 3-4 toxicity. continue
tr€ahDent with a 209/o Doxilo dose reductiou.. Maintain the
Carboptatin dose.
3
$ainfirl erytherna.
ederua, or ulcers. and
cannot eat)
Delny dosing up to 2 rveeks or until resolved to Grade 0-1.
Decrease Doxil@ dose by 2Ao/o. Maintain the Carboplatiu close. If
afrer 2 r,veelcs ttrerc is no resolution, patient will be reruovecl from
thejtudy.
4
(requires parenteral or
enteral support)
Delay dosing up fo 2 rveeks or uatil resolved to Grade 0-1.
Decrease dose Doxil8 hy ZO%. Maintain the Carboplatin dose.If
after 2 weeks fhere is no resolution, patient rvill be rernovecl frour
{e study
7.4.3 Bevacizumab
There are flo tedrrctions in flre bevacizrunab dose. If adverse events occru'that requir.e holding
bevaciztunab, the dose will rernaiu the saure once treatment rcsuues.
Atty toxicify associated or possibly associated rvith bevacianmab treatment should be
managed according to standard rnedical practice. Bevacizurnab has a terminal half-life of 2 to
3 weeks, therefore, its discorrtiutmtion results in slow elimination over several rnonths. There
is no available antidote for bevaciaunab.
Patients should be assessed clirrically for toxicity prior to, dtuing, and after each fufrision. If
urunanageable toxicity occuls because of bevacizuurab at aoy time during the shrdy,
freatment with bevacizumab should be discontinued llowever, patients may continue with
doxil or epirubiciu ald Carboplatin h'eatment if admiuistration criteria are rnet.
Adverse events requiring delays or pernarlent discontimmtion of bevaciztuuab ale listed in
Table 7.4.3.
Regafdless of the reason for holding study dnrg b'eatrnent, the maxinrum allowable length of
treatneut internrption is 2 months.
Version Date: 1O/17i13
I
- 1t -


A Phase II Trial of Doxil . Carboplatin zuld Ber,'aciamab in Triple Negative Preliogsly Urtreated Metastatic Breast ca,cer
1 .4.3.1 Infusion Reaction
hrfusion of bevaciztunab should be interrupted for patieuts who develop dyspnea or clinically
sigificant h1'pote$sion. Patients r,vho experierce a NCI CTCAE v. 3.0 Grade 3 or 4 allergic
reaction / hypersensitivity" adult respiratory distr.ess sl,ndrome. or bronchospasrn (regarclless
of grade) will be discortinued fiom bevacizumab treatment.
The irlftisiorr shorild be slotved to 50% or less or intemrpted for patients who experience any
iufruion-associated syrnptoms not specified above. WIr.o the patient,, ,y*pto*s have
complefely resolved. the infrrsion may be continued at uo more thao 50% of the currently
being received nate prior to the reaction aud increased in 50% increments evety 30 rni,.tes if
well tolerated- Infusions uray be restartecl at the frrll rate duiug the next cycie (see Sectiol
7.3.3).
Table 7.4.32 Bevacizumab Dose Management Due to Adverse Eyents
Version Dale: l0/17/13
-
Event
Hypertension
No dose modifications for Grade
Grade 3
Action to be Taken
I or Grade 2 events
Bevacizur,rrab tuay be contilued in coljguction with stadard anti-
hlpertemive therapy at the lnvestigatoi's discretion. Bevacizumab
should be held for urcontrolled orilurptoumtic hyperlension present orr
the-{1y th{ the bevaciztuuab dose ii to ue givet. if gp is not controlled
to 150/100 nuuHg with medication rvithin T ruonth, discontiuue
bevacizumab.
Discontinue bevaciztnuab.
Grade 4 (includirrg RPLS
(confinued byMRI) or
hyperlensive encephalopathy)
Ilemorrhage
No dose modif,cations for Grade
Grade > 2 puhnonary or CNS
hemorrhage
Gmde 3 nonpulmouary and non-
CNS hemon'hage
Grade 4
I or Grade 2 uonpuh:ronary and non-CNS events
Discontirrue bevac izumab.
Patients who are also receiving ftill-dose anficoagulation will be
discontinued fi'orn receiving bEvaciztunab.
Atl o$ter patients will have study treatrnent held turtil all of the following
cntena ale il]et:
o The bleeding has resolved and hemoglobin is stable.
o There is no bleeding diathesis that would increase the risk of
therapy.
o Theie is no auatomig or pathologic condition that significantly
iucreases the risk ofhernorrhage reculrence.
Patients who experience a repeat Grade 3 hemon:hagic event lvill be
discontinued fiom receiving -bevacizuurab.
Discontinue bevacizuuab.
- )1 _


A Phase II Trial of Doxil . Carboplatin and Ber.aciaunab in Triple Negative Previously Unseated Metastatic Breast Catrcer
Table 7.4.3 Bevacizumab Dose Management due to Ath'erse Events (continued)
Yenous Thrombosis
[Note: Patients rvith lung carcer placed on anticoagulant therapy for a thrornbotic event should be
discontiuued froru receiving bevaciztrmab]
No dose ruodifications for Grade l/2 events
Grade 3/ Asyrnptomatic Grade 4
Hold stttdy dnrg heatureut. If the plarured dumtion of ftlll-dose
anticoagrdation is <2 weeks, sfudy dnrg should be held rurtil the flrll-dose
anticoagulation period is over. If the plarured drration of full-dose
anticoagulation is )2 weeks, silrdy drug maybe lesuned during the
periotl of firll-dose anticoap5ulation if all of the following criteria are ulet:
. The patient mrut have an in-rauge INR (usually between 2 and
3) on a stable dose of warfariu (or other anticoagulant) prior to
restarting study dnrg treaturen{.
e The patient must not lnve had a Gmde 3 or 4 hemon'hagic
event while on anticoagnlation.
r The patient rnust not have had evideuce of tumor involviug
major blood vessels on any prior CT scan.
Discontinue bevaciauuab.
Syntptomatic Grade 4
A$erial Thromboembolic event
(Angiua, nryocardial infarctioa, transieut ischemic attack. cerebrovascular accident, and any other aftedal
tluonboembolic event)
Any grade 
Discontiuue bevacizrunab.
Congestive Heart Failure (Left ventricular systolic tlysfunction)
No dose modifications for Grade I or Grade 2 events
Grade 3 
Hold bevacizuriatr until resolution to Grade < I
Grade 4 
Discontinue bevaciaunab.
Proteinurla
No dose modilications for Grade I or Grade 2 events
Grade 3 
Hold bevaciaunab treatment until < Grade 2, as determined byeither
(IrpC> 3.5, urine collection > 3.5 UPC ratio < 3.5 or 24 hr collection < 3.5 g
g24br, or dipstick 4+)
Grade 4 (nepluotic syndrome) Discontimre bevacizurnab
GI Perforatlon
Discontinue bevacizunab.
Vexion Date: 10/17/13
-
-?5-


Table 7.4.3 Bevacizumab Dos. Munugem
Bowel Obstruction
Grade I
Grade 2
Gmde 3/4
[:lJ1lXqltient on sr*dy for partial obsrru*ion Nor requiring medical
llttetventroD.
Hold bevaciz*mab for partial obstructiorr requiring medical
intervention- Patient ruay restarl,rpoo "ourpiitil"lJ"ti"*
Hold bevacizu,ab for complete obshrrction. If surgery is ,ecessary,
patie,l uray res.tafi bevacizru,ab after flrll recovery i;il;,iG;;y, airct at
urvestr gator'' s discretion.
Wountl dehiscence requiring
medical or surgical therapy*
other unspecilied Bevacizumab-Related Adue"seEv.nd
Grade 3
Grade 4
Hold bevacizumab until recovery to < Grade 1
Di scontinue bevacizrunab.
jl93lllDoxil 
' carboplarin zutd Ber'nciauuab i, Triple Negative preriously untreared lr{erastatic Breast carcer
7.4.4 Epirubicin
h the eveut that there is a shodage of doxil. patients will be allowed to receive tr-eatrnent
with epirubicin.
Diarrhea and Stomatltis
Anfidiarrheal medicatioil nray be used at the discretion of the hvestigator. Diaruhea ans
stomatitis must rehun to < Grade I before adruinistration of the next cycle. If. after a 2 week
delay, dian'hea and/or stomatitis have uot rcsolved, therapy must be discontinued.
Grade I and Grade 2: No dose reductions.
Grade 3: After the first episode of Grade 3 diarrhea andlor stouratitis, decrcase the
epinrbiciue dose to 48 mgfiu2. Mai*tain the ca'boplatin dose.
Grade 4: If the patient experiences Grade 4 diarrhea and/or stomatitis, therapy must be
discontinued.
Hepatic Dysfunction
Therapy must be held for a > Grade 2 increase in bilrnrbiu (>1.5 x [ILN) or Gracle 2 incrcase
itt SGOT (' Z.S x IJLN), If the increase is not due to metastatic ctisease, therapy may be
restrmed at full dose if the following criteria are ruet:
o SGOT must rehul to < grade 2 (SZ.S x I-ILN) withiu 2 weeks: and
o Bilinrbin must retum to nonnal rarge for the lab within 2 weeks.
Version Date: t 0/l 7/l -l
-
-:6 -


%arrttBer.acizruuabirrTripleNegativePreliorrslyUntreated]vtetaslaticBreastCancer
7.5 Concomitant Medications
Iu general. concomitant ruedicatioris and therapies deemed necessary for the supportive care
atd safetyof the patient are allorved. All cotcoinitant nedications must be docrurreated in tlre
patient's medical rccords.
Low-dose aspirin (5 325 rng/d) may be. continued in patients at higher rjsk for afierial
throruboembolic disease. Patients developing signs of arterial ischemialr bleeding on study
shonld be evaluafed for possible bevaciztunab dlscontinuatiou per Table I .ii, a*uciauuab
Dose Manageurent Due To Adverse Events.
7.6 Suppor.tive Care Guitlelines
All supportive lrleasues consistent with optiural patient safety r,vill be utilized, including but
not lirrited to antiemetic uredicatiou, hydration, transfusion support arrcl antibiotics. No other
chemotherapy, imuruttotherapy, hornronal caocer therapy, radiatior flrerapy, surgery for
cancer, or expedmental medicatioris will be penuitled while the palients are iarticipatiug iu
this study.
Pafients may be started on erythropoietin (Procrit@lAlanesp@; after the first cycle if
clinically oecessery.
The use of G-csF {br pfevention of ueutopenia is not allowed. Use of G-csF or equivalent
is to be used in accordance with ASCO Guidelines.
7.7 Adherenee/Compllance
Patients who fail to present for treafiuent appointments may be rcmoved frorn the study.
Patieuts that are routinely non-compliant to protocol requilenrents may be iernoved at the
discretion of the Investigator.
8. Toxicity Monitoring antl Adverse Event Reporting
All patients rvho receive one dose of protocol theripy will be evaluable for assessment of
toxicity- Prior to each cycle the heating physician or fheir desigrree rvill fully assess the
patient's conditiol-'i,vith respect to possilie h'eahneut related toxicities. All adverse everts,
whether observed by the physician or reported by the patient, occuning durilg the active
portion of therapy, or up to 30 clays aftil the tait doue of treatruert *"-itt t. graded by a
numerical score according to the NCI's Comruou Tenuinology Criteria for Adverse Events
(CTCAE). Versiou 3.0 
a,d reeorded in the
patient,smedicalr.ecord.Toxicities1i,.tuo@ties)willber.q>or1edas
outlined iu the data captue plan.
A preexisting condition is one that is plesert at the start of the sfucly. A preexisting condition
will be rceotded as afl adverse event if the fiequelcy, intensity. o, ilr" character of the
condition tvorsens duing the study period.
\iersion Date; 10/l 7/13
-


ryaldBevaciauuabirrTripleNegativePreviouslyUntreatedIuetastaticBreastCancer
8.1 Adverse Event Reporting Requirements
An adveme experierlce is defined it uoy uuiufended or alxrornal clinical observation that is
uot of berrefit to the patient' Either the conditioil was not preseut prior to exposlre to the
shtdy therapy. or it has worseued in intensity or frequerr.y ttto*ing exposur€ to rhe study
therapy.
AII 'turexpected" (see sectiou 8,4) and/or "serious" (see section g.2) adverse events
occurring durilg the active portion of therapy, or up io 30 days after the last dose of
ffeatrnent, will be reporled to the 0HRS at (732) 235-7i77, Eve.nts will be promptlyreported.
in lvriting, to the local IRB in accordance with iRe policy. lf u,t*rt, occrus the IRB will be
notified within Z4-hours of injtial receipt of infonuation. AII other sAEs must be reportecl to
the IRB withil tlu'ee to ten days of initiat receipt of infonnation. written follow-up reports
are requircd rvhen additiorlal infonnation is neeied to frrlly ciraracferize the event. copies of
each report sent to the IRB will be kept in the study,"g,rtuto,f nt..
In addition fo reportiug to fhe local IRB, reporting to exter:ral bodies such as indgstry and/or
flre FDA may be required.
CINJ0G afflliates wiII report all SAEs to the oHRs. oIrRs wiII be responslble for
forwartling SAE reports fo all appropriate goqps as needed
Reporting SAEs using commereially available drugs:
In addition' any unexpected (ror listed rn he. pockag"e insert) serious adverse events fhat are
assoclated (defluritely, probably or possibly relatecl) r.vith the u.se of Doxil and Bevaciammb
must be rcported to the FDA rvithirr 7 rvorking tlays usurg a FDA Folrr MedWatch 3500
forn http://www.fda.govfinedwatch,rsafetvl3SO0lpdf tr"* * t]soo-roe-0l7s).
Version Date: 10117/1i
-
Expedifed reporting requir.ement fo
FDA MedWatch form 3500:
repor"t is to be submitted to the FDA wittrin
-?8-


A Phase rI Trial ot'h;ril . ('alboplarifl ald Be$al'iannab iu Triple Negative prer.iously Unh-eared r,tetasratic Breast cancer
\rersion Date: l0/l 7/l3
-
8.l.l Reporting of serrous Adverse Events to Genentech, rnc.
Investigators are required to teport to Genentech Drupi Safefy ANy serious trcatment
emergent adverse event (STEAE) as soon as possible.
A STEAE is any sigrr" symptotu or nredical corrdition fhat emerges during Bevacizumab
ffeatrnent or dt['ing a post-treahrrent follow-up period tJmt (l) rvas not pr-esent at the start of
Bevacianmab trcatment and it is ttot a clronic condition that'is pa* ofihe patierrr;s medical
history. oR (2) was present at the starl of Bevaciztunab treatrnert or as par-t of the patient,s
medical. history but worseted iu sevedty ald/or fiequency dtuiug therapy, AND that meets
ary of the definitio.s of a serious adversi event (see Sectio, s.2).
AII srEAEs should be recorded on a Medwatch 3-500a Fonu and faxed to:
I
(Please use tlre safety rcporting fax cover sheet provided in the shrdy operatiols manual for
your fax transmission)
IIt addition to complethg appropriate patieut deurographic and suspect medication
iufonnatiou' the rcpolt should include the foltowinf information within the Eveut
Description of the MedWatch fonn:
r 
Treahnent rcgiureu (dosing frequency. corubination therapy)
o 
Protocol description (andnumber, if assigned)
o 
Descriptioa of event" severity, treafinert, and outcome, if lorown
. 
Supportive laboratory results and diagnostics
I 
luvestigator's assessment of tlie relationship of the adverse eveut to each
investigational product and suspect uredicatior
Follow+rp infonua tion :
a: This includes aII deaths *itt in
::ff*::_:l^iT]Pld"i.. Anv death that occtrs morc rhan 30 days after rhe last dose of rreatmenr
. ueatlnent
with a comruercial agent(s) a*d is attributed (possibly. prouatrry,E{initely) to nre aferilsj a,o is not
due to cancer recureuce must be reported according io tt . i*t-,r.tions above.
b Protocol-speciric experlitetl ,'*po"tiog requirements: All SAEs rnust be repofied to Genentech.
Iuc. as outlined below.
All CINJOG affiliates contiaue to
all SAEs ro the OHRS.
-29-


A Phase rI Trial ofDoxil . carboplarin ancl Bevacian,ab i, Triple Negative prel,iorsly untreated Metastatic Breast cencer
f;fr1*ff'J:ilffilon 
ruv be aclded to a previousrv subrni*ed reporr bv any of the
r 
Adding to the original Medwatch rcport and submirting it as fbllow-up
o 
Adding supplemeutal surrunary infonnation aud subrnittilg it as follow-up rvith
the original MedWatch fonn
r 
Suurmarizi[g nerv infonnation and faxing it with a cover letter inclgdiug patie,t
identifiers (i'e' D.o.B. initial. 9a1ien1o*irbo';. protocol description a1d munber,
if assigned, suspect drug, brief adverse "u*iri o.."ription, and notation that
additioual or follow-up iufonnation is being subrnitfed 1rrrc prti.ut ide,tifiers are
important so that the new inforuration ir uaiJto tlre ,oueci *iirr ,p"rtl
occasionally Genentech flray contact the reporler for aclditional infonnation, clarification, or
crurent status of the patient far whom and adverse event was reporled.
Assessing Causaliry:
Investigators are reqEired to assess rvlether there is a reasotable possibility that bevacizurnab
caused or contributed to ao adverse eveut. The followiug g.o.rrf guidance *uy u. ur.a.
I'er" 
if the temporal relatiorxhip of the clirrical event to bevacizru,ab ad'rinistr.ation
makes a camal relationship possible, aud other chugs. therapeutic interyeltions or
underlying coilditiotts do not provide a sufficient explanation for tle obse.ed
evenf-
No: 
if the femporal relationship of the clinical eveut to bevacizurrrab adruirristratiou
tuakes a eausal relationship urlikely, or other drugs, therapeutic ipte,rventiols or
underlying conditiotts provide a sufficient explalation for the observed event.
8.2 Delinition of Serious Atlverse Events (SAEs)
A serious adverse event (experience) is one occturing at any dose level that resulfs i, any of
the following outcoures:
. Death
' Life-tbreate,ing- imrnediate risk of death from the reaction.
' 
Requires inpatient hospitalization or prolongation of existing hospitalization.
' 
Results iu persistent or sigrrifica,t crisabilirylincapacity.
. Results in a congenital anomalyr,birth defect.
' 
ReEtires intervention to preveut one of the outcoures listed in this defurition.
The definition of serious adverse event (experience) also include s itrportant nrcdical events.
Medical aId scientific judgurent will be exercised in deciairrt whether expedited reporlilg is
appropriate in other sittmtions, such as iurporlant meelical *r.nt, that umy,ot be im're4iately
lifetlueatening or rcsult in deatli or hospitalizatior but urayjeopardize the patieut or may
require interventiott to prevettt one of the other outcomes liste in the defuritio, above.
These events will usually be considered sedous. Exarnples of such events are intensive
Vengion Date: l0/l 7/l j
-
-30-

ICF_003.pdf: 
 
 
Official Title: 
A Phase II Trial of Doxil, Carboplatin and Bevacizumab in 
Triple Negative Previously Untreated Metastatic Breast 
Cancer   
NCT number: 
NCT00608972 
Document Type:  
Study Consent - Main 
Date of the 
Document: 
10/07/2011 
 
 


CONSHI\IT TO TAKP PART IN A RASSARCH STI.'I}Y
Concer Institute of New Jer*eY
A Phase II Trial ot'Doxil. Carboplatin and Bevacizumab in'l'riple
Negntive Previr:usly untreated Metastatic Breast Cancer
'l'itle of Study:
Principtl lnvestigltor:
lntroduction
This furrn is part of an informed consent procsss fur o reseflrch study and it will give infarmation that
wi1 help yoo ro decide whether you wish to volunteer fbr this rcsearch study. It will help you t'o
undErstand what the study is about and what will hoppen in the couse of the study'
Ifyou have questions st any time during the research study, you shtruld teel tlee to ask them and should
expect to be givcn answers that you cornpletely understand'
After all of your questiono have becn answersd, if you still wirh to take psrt in the study' you will be
asked ta sign this informed consent firnn.
The str.rly doctor (the principal invcstigotor) or another msmber of the study team (an investigntor) will
also be asked to sign thir i*th*ed conseni. You will be given a copy of the signed consent forn'l to
keep.
you arc not giving up eny of your legal rigfits by volunteering fur this research study r:r by signing thi*
cnnsent forrn,
Funding CompanY of StttdY
The doctor and/or Institution is the "sponsor-investigator" of this Study. This mea$s the doctor and/or
Institutisn is the one who both initiatus zurd actually conducts, alone or with others, a study, that is"
under whose immediare directi6n thc study drug is adrninistered, dispcnsed, or used'
Ocr 7 ?.ail
IFFEOTIL ExPIHE$
*: Nt 2ffi6 I ? 2012


Titleof$tudy:Al'hnrcllTrialol'Dtlxil,Clarbpplulinandli*vacirumsbin
lriple ),legati ve Il'eviorrsly l)ntrcated Metustatic Breasl
Cancer
A phannaceuiical comPanY,
being paid to coniluct this study according
is * suppnrter CIf thi$ re$eerch study' Th* study doctor is
to a butlgct. The budget covers some of the costs of
collecting the infl
will be supplied bY
r#hy have I bren rsked to partieipnte in this study?
you are being askedto take pur in this study becauu* yrlo have metaststic {spreadto otherparts of the
body) breast sancsr. ffris type of caneer is usually treated with drugs called'ochemotlrcrapt''(dnrgs used
tokillcancercells),yourtypeofbreerst.un"*risnegativefbraproteincatledHER2/neu' Yourtypeof
breast c.ancsr isqlso o*guti* for es*ogen r*"*ptorrlER) uncl piogesterone receptors (PR)' HER'2lneu'
ER und pR are pafi of a family of rcceprurs fi:unrl on hoth cancer ancl normal cells. This family of
receptors is inrportant for cell gto*L and is fbund in rnany tumor types' The body is made up of tiny
building blo*ks called cells thal eontrol every body function. Some cells stop worki*g as thsy xhould
*nd booor,fre canserous cells. unlike healthy *lu*, "***r 
cells grow and multiply abnormally'
destroying bcdy organs.
The purpose of this research study is to look at the effectiveness of a s.onrhination of doxil' carboplatin
and bevacizumab on m$isstatic breast cancer'
This stldy is being conducted fnr the tglltlwing research purpss*s:
r To fintl out what effects, if any, rhe study drug hus on yCIur cflncqr. For instance, will the study drug
cause your tumor(s) to shrink or stop growing?
r To test the safety of the snxly drugs and to ser: whnl alTee ts it has on you. For instance, nrc there any
side effects? If so, what kintl of siae e&cis does the study drug cause? How severe are the side
ellb*ts, and how ollen do theY occur?
r To see if the study drugs have any effcct on keeping your diseass from getting worse'
r To mr:nitor your heaith and overall well-being rvhile taking the study drug,
Doxil is used in the treatment of solicl tumors including breast cancer, bladder cancer, small cell lung
s{mcer, thyroid c&ncer! gastric canccr} malignunt lympli,rtras of b'oth }Iodgkin &nd non-Hodgkin type,
anrl auut.] lymphocytic. (lyrnphublastiu) leukemia'
If thse is a shortage of doxil you will be *blc to receive tr$atment with epirubicin' a commercially
available drug that is sirnilar to tloxil. Epirubicin has been appreived by the FDA for the treatment of
breast cancer. You will qt.rntinur:
:-au othqr srudy treatments and sat'ety monitoring ss outliDed in
il%J'- [I} 
'If L'fix"'i*Y,'ffi 
ac i zum ah
IFFffivAL ExPIRE$
AU6 1 ? 201?
this consent.
l)aet.l ol'lt)


Bevasizurnab is an antibndy direeted against vasculu endothelial growth factor, or VI:fiT. VH0F is a
potent, specific growth factor with * *"ll-d*tined rolp in normrl and abnormal blood vessel formation.
it i* pr.**rt in a wide variety of nonnal tissues, hut is prsduced in excess by most solid cancers
(tumors). In the setting of cancer, VEGIr promotes the growth of blood vessels that bring nukients to
tr*rnor cells, ln studieJwith laboratory animals, trevacirumab inhibits the growth of several dilTersnt
gpes of human cancer cells, inclurling colon cancer cr:lls, hy blocking thu elfeets of VHGF'
Bevacizumab rsceived o'accelcrnted" approval by the FDA fur the trsetmsfit of met&$tetic breastsancsr
in 200g based on posirive e*rly findings from a large clinical trial that bevacieumab in combination
delayed ths progressinn of breest cancei significantly longer than when chemotherapy r*as given alone'
Final approval, htrwever, was contingen{ on two adrtitional stutlic$ in metastatic breast caneer
demonstrating similar findings. Recent malysis of &e two trials did not show the sanre benefit noted in
the original rtuay. Because oith* potential side elTects ass$cinted with the drug, nnd thE less signific*nt
benEfit noted in the two conlinnatory studiss, the F'DA is cunsitlering withdrawing approval for the-
treetment in breast canser. The FDA has encouraged, however, trials to determine populations of
patients for whom th* elrug's benefits may cxceed ihe risks. Triple neg*tive brenst canser may be a
sultype *f breust cancsr inlvhich the benefits outweigh tlre risks. Therefrrre, we da not know how the
intbimation Jlorn the other stu{ies applies to you with advanced triple negative breast cancer'
The FDA ha* approved carhoplatin for use in treating cvarian cflncer. Carhoplatin is al.so used ta treat
various typ., oi'canc$r, tt is o chemotherapy drug that contains platinum. It is used alone or in
combinaiion with other rnsdications to slow or stop cancsf cell growth'
Who may or mey not partleipttc in this study?
In order to take part in this study, you nrust lravc the following conrlititltts:
r you must be a woiltan with a diagnosis of metastatic breast cancer with none of the prtrtein
HER2/nue or estrogen receptors ([tt) or prr:gesterone reseplors (PR) presenl.
r You must be 2 l8 Years old,
. you must not havE received chemotherapy {drugs given to kill cancer cells) for mstastatic brenst
clln0€r.
r your cencer must bs able Io be measured, either by a physicsl examination or rcview of an x-
ray'
o You c&nnot be pregnant or nursing a baby while on tiiis srudy.
. If you ane able to beco,rre pregrant and have a batry. you nlust have a pregnancy test that is
negative (meaning you are not prBgnanl,t an<I agree to use el'fective birth eontrol, (e'g',
obitinence, intrauirlnc d*vice, nrul .ontr**eptives, barrier device with sperneicide or surgicnl
strriliratiog) during trs*ltinent antl I'rlr three months afier conrpleting fieaturert.
e your heart must bofunctioning normally. The study docior will son{irm this through standard
tests u$ed to meaqure hean function.
l,itle of study: A ph*se II Trial {)f Derxil , cturboplutin ul}d l3evncizumab in Triple Negarive Prcviously untrealed Met&slttiu Brca$t
Cmcer
Principal lnYestigst$r
How long will the *tutly take and how many patients will particip*tc?
This study is estirnated tu enrull patients over two years. You will uontinue treatment until your disease
worsens(prcgr-rffi
NJ 2IO?
&tlil ? iole
Itlcnenr 
lAppH$ffiff*
ocT 7 ?011
fft
fg IeCe lrv'l
Fagr.'r 3 of I
1"he study doctor


Title of Study: A phnse ll Trirl of $oxll , Corboplutin nnd Bcvneinrmsb in Triph }legative Pmviously Untraated Mctustalit llrsast
C*ncer
r#h*t witl I be fl$k€d to tlo lf I purtiuipnte in this rescnrch sturly?
Beforc you may take part in this study, you rvill need to anslryer questions and have the following te$t$
and examinadCIns tCI see if you are eligible. This is called $crBsnin&, It is irnPortant thst you answsr illl
que$tio$ honestly and eoinpletely, If anything changes bef"ore or during the study, you must tell th€
study doctor, Based upon the &n$wers to the*c-questiins and the rcsults of the tests and examinations
which Save been performed there is a possibitrity thar ynu mey not qualify for participation in this study'
ln some insta$ce$, certain t$sts or procedures conducled during the study rnay have to be repeated' For
example, this can occur if *n,rr* o* all of tha results are unusahle' Also, you may be asked to have
additional tests or examinations. For exarnple, this can r:rcour if an unexpeeted medical event occurs
duri*g the study, Before you begin trsotmeni. you will need to have tire following tests and procedures
done:
will decide if the treatment is n0 longer of benelit for you and if you should come offof the study'
About 50 patients total are expeqg! ro rake part in this study, About l0 patients are sxpected tu take
part in this studY at the
A history and PhYsieal exam'
you will be asked about ths Extent of'your physical aotivity and how you are generally feeling"
Your weight and height will be taken.
you will have bloqrd ir*,,vn using a smoll needle or plastic tube, to check your blaod cell uounts,
your blood chemistry, how yauiliver and kidneys are workipg ald your electrolytes'
You will have a urine test to monitor the level of protein in your urine'
You will have an sleusgardiogram {onc (also known as "[CG" or "CIKG")' This is a painle ss
peprr tracing of your heart's normal eleotrical activity'
you will huve a special heart test sallsd a MUCA silan" These tests will tell the doctors how
well your heart works &s a pump. This is important, since some of the drugs used in this study
rnay affect your hcart nluscle. 'fhis test will be repeated several tirnes during the study'
A MUGA scan msa$l;Igs how well yr:ur heart pumps bloori' During the MUGA scan' a
radioactive marker is i4iected into a vein- and special eq*ipment is used to measure the
pumping caPacitY af Your heart.
I
t
I
a
a
t
If your doctor feels you neetl it, you rnay have to h*ve a CA]'scan or MRI
looks at the organs in Your bodY).
If you are able t0 become pregnant and have a h*by, you must have a I
wi'tfuin one wEek ot'enrollment. "l'he results of this test must be negadve
In addition during the study, you will have:
. Blor;d tests bslbre trcetment and weckly during the srudy. A complete blood count (CBC) will
be checked weekly to make $ure y$u have safe ievels of the differeut types of blood cells in your
body'andtrrsechowthctrcatmcl)tcftbctsatypcufblotW
, (special tests which
pregl}ency test taksn
0[T ? 20fi
m-J;, 
;;;1; iififfilfif,\ r"'** + *,"
tr o'iit?u$lt I
'-rI


Title of $tudyr A phme II Triul of Doxil , carboplatir:r ond llcvaciz*mab in I'riple Neg*livc Prcviously unlreated Mote$0tic llr0est
C&ncsr
r Other bisod tests including chen:istries and
effects frorn the trealmellt. You rvill have a
liver {iu:ction test$ rvill he d*ne to check fi:r side
urine test belbre treatment to mottiteir the level of
pnrtein in your rlrine.
A CA'Iscan (computed axial imaging) or anMRtr (Magnetic Resonance Imaging) may he done
eyery S weeks whilr you ff* on thi study if the study doctor {bels it is needed. T}:e CAT scan or
MRI will be dona to look st the size *nd location (place) of tumors.
you will also need to have an ECG ($lectrognrdiogram, also known as an "[KG" * a painless
paper tftruing of the heart's nunnal electrical activity)'
you will have a Ml,$A ssan every l2 weeks and one month alter your last treatment with the
study drug combinntion'
The treatmont rchedule l* ss followu
lf you decide to take part in this study and are able to join based on ths abovo criterin, you will hnve the
following treahrent.
you will have the clemother*py (drugs used to kill cancer cells) with the drugs doxil, carboplatin and
bevacir..umab. A geatm*ot p*iin,t *itt t* 28 days long. This period is known as fl oncyclen'' All
medications are given using a small needle or plastic tube into one of your veins'
carboplatin snd doxil will be given on Day I of e*ch 28 day cycle.
Bevacizumab will be given on Day I after you have received carboplatin and doxil' Bevacizumab will
also be givsn by itsslf on D*y 15 of each 28 day cycle.
,L:"+"y"r *
carboplatin
r 
12-14
15
t 6-?8
X 
I No drugs
X -*l 
given
No 
drugs
given
doxil
trevaeieumab
X
X
X = dnrg is taken
You will continue to receive these medicati*ns unless:
o You have ssvere, ssrious and/or excEssive side effects'
r Your cfilcer becomes worse.
r You wish to stop taking part in this stutly.
r Your tluctor &sls it is not in your best interest to eontinue this trettment"
TLEASN NOTE; T}IERtr IS NO PLACEBO (INACTIVE DRUC, OR'(SUGAR" PILL) USED
IN THIS $TUAY. ALL PATIANTS WILI, R.$CEIY$ ACTI"IAI, DRT]G.
I{hlt are thr risks rntl/or tli*comfsrts lf I chote to pnrticipatt in this etudy?
Any risks listed may be serious enough to restilt in hospitaliz*tion and/or death'
tJ0 I ? ?0lt
Ptge 5 *f I(r


"Iirlo $f Sludy: A phrsc Il Trial of Doxil , Corboplatin and 8*vocieum* in Triple Negotivc rreviously Unlreakd Metaslatic llrtost
The followlng *re sido effects, whfuh msy oecur with the drug c$rboplr4nl
Likeh{:r l.owered nurnber of red blood cells. Red blood cel]s carry oxygsn to the organs in your body' A
lowered number of retl cells is known as anemia and can rnake you leel very tired and
$0rnctirl}es shtlrt ot' hreath.
r Lowcred nurntrer of white blood ceils. White blood cells help to prevent infections' A lowEred
numbrr of whiie blootl cells may makc it ea$isr fur you tCI g$t sn infection.
r Lowered number of platelet cells. Platelet c*lls hetp your blood to clot. A lowerBd number of
platelet cells may make it easier for you to bruise {"Black and blue" marks) sr bleed'
r Nausea (a "nsick" feeling in your stomach).
, Vomiting.
r Weekness
r A very tired &eling
[,rw L,iklv:
r Diarrher.
" Constipation
r Hair toss, not only llom your head, but also ftom your underarms, fhce, eyelashes and pubic
&rea"
t
o
a
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t
a
a
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I
You may not lbel like eating.
lfumbniss, tingling, and/or pain in yorx'hands and feet. This is usually reverfsible.
Changps in your levels of sodium (solt) and potassium in your blood.
Mouth sorcs
Yellowing of, the eyes/skin
Dark urine
Changes in the amou$t of urine
Pnin/rednesdswelling at the injection sito
Skin rash
Itohing
Shortresr of brqath
\Yheczing
Allergic ieactions
Hearing problerns (e.g. ringing in the ears, hearing loss)
Rnre:r Mouth ulcer$ or blisters
r Blurred vision
The folluwing art siek: clfucts, which nrny huppen with the drug {gll:
!=tkeh
. 
Nausea
r Vorniting
mn6vm ExPIHE$
AU6 t 7 ?il12
ocT ? t011
Fagc (r uf Nf


litle of litudy: A phrse ll rrid of Doxil , carboplarin and lluvacifiumab in "liiple Negative Prcvinusly untrealed Metastaiic Breast
Asthsnia (fatigue, weaknffi$, tirednoss)
Anorexia (loss of aPPetite)
$ianlrea
Constipction
Neutropenia (fever)
Thromiocytopenia (abnormal drop in the number of blood cells involved in furming blood clots'
Ibese cells are called Platelets)
r Anemia (below normal levels of rotl blood cells or henroglobin, or
t
t
a
I
t
)
a
a
both, whiclt can be caused bY
many different conditions, including iron deficiency)
Rednesso pain, blistering of palms and soles of feet
Hand-faot syndrome 6ffS;. Ir usually occur$ on the palms erf the hands and soles of the fbet' It can
also occur on other parts of the borly where yow clothe$ miry be tight or where fiiction, pres$ure'
rubbing, warmth, andlor sweating osc$r.
Siomatitis, u mouth irritation characterize by inflanrnration or ulcers (sores)' Sorne common
symptoms"o{ stomatitis include mouth $ores. clry swollen tonguc, dry crackcd lips, pain or buming
in the mouth, inability to eat or drink, or tliffrculty swallowing.
Less Likply
r Mild hair loss
r Flushing
r Chills and fever
r lrrevergible weakening of the heart muscle (with higher doses) or heart problem such as heart failure
or damage to the hesrt muscle
Rare b|lt serious
r Shortness of breath
n Tightness of chest and throst
. Erythema multiforme: a ra$h consisting of welts, somedmcs with purple or blistered are*s in the
centar with itching, fcvero general ill tbeling
r Srevens-Johnson iynaro*i: potentially deadty skin disease rrsulting in facial awelling, tongue
swelling, hives, s*n pain, red or purple skin ro*h,. blisters on the skin, mu&o$s membranes
(especially mouth, nose e&d eyes), shedding af the skin
. io*i. epidermal necrolysis: u lif* thr*ut*ning skin di*ordsr that cau$ss blistering and pceling ofthe
top layer of the skin
Thr following are sid* effsctsn which rnay happon with tho elrug Bev*cizumsb (Avrstino):
Likely:
r Dinrrhea
. Nausea or the urge to vomit
r Vomiting
r Fatigue or tiredne*s
APPROVEO
OcI ? 2011
AU0 1 ? u012


fitle of $tudy: A phus ll ll?l*l af lloxil , cmboplarin and llovacir.umsb in Triple Negarirc llrcviously untreatcd Mctsstatic Br*{$l
I"ieadachc or head Pain
lligh bloeid prsssure
lpss Likely;
r Lack of enough rcd blood cells (anemia)
. Fasl heartbeat usually originating in an area located above the ventricles
r Feeling of spinning or whirling
r Belly pain
r Inflanrmation (swelling and redne'ss) of the largo bowel (colon)
r Con*tipation
r Heartbum
r Bleeding in some organ(s) of the digertive tract
r partial or complete Uto*t*ugr of the small andlor large bowel. Ilcus is a functionsl rathsr thnn
acrual blockagc of thc bowel.
r lrritation or sores in the lining of the mouth
r Reaction that can occur rluring or following inlirsion uf thc drug' The rcaction may include
fever, chills, rash, low blood pressue, end difncul$ breathing-
r Chest pain not hEart-rsl&ted
r Pain
r Allergic rcaction by your hody to the drug product thnt can occur immediately or may be
delayetl. Th* reactic,n may include hives, low blood presisure, wheezing, swelling uf the throat,
and difficulty breathing.
r Infection
r lnfwtion (collection of pus) around the rcctum
r Prematurs opening of a wound along nugieal stitches afler surgery
r lnurasEd blood level of a liver alryrne (AL"I$GPT)
r lrrcreased blood level of a liver or bone enzyme (alkaline phosphatase)
r Increased bloocl level of o liver enzyme (AST/SOOT)
r lncreased blood level of a liver pigment (bilirubin) n{ten a sign of }iver problems
r Incrcased blood level of a henrt muscle protein (troponin t) inrlicating damage tCI the heart
muscle
r Deueased numberof a type of white hlood cell (neutmphillgranulocyte)
r Weight loss
r Decrease in the total nunrher of white blood cells (leukocytes)
. Loss of nppetite
. Joint pain
o Abnormal changes in the groruth plate that rnay afTect the growth of long bones in very young
ehildren. 'lhis side effect oppeared tn be reversibls afler the treefin$nl wa$ stopped but has not
been assessed with lonpterm use of the bevacizumab drug'
r Muscle pain
s. un$te&dinss
Pagrl I ol l$
a
a
r Dizziness (nr sensatig-tl
flPffisl gxPlREs
G1??011
APPHOVEN
ocr ? ?0lt


i
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I
'l'itlc of $tudyl A Phue tl Trial of Doxil ' Ca$oplatin *nd Bevacizrrntab in lripl* Negtlive Pr*viously linlrouted Metlstalic l]rcast
Fainting
Suddcn deorease ofkidney function
Bl00d in the urine
More prctein leaking into the urine than usual, ofter e sign of kidney disease
Bleeding in the voginn
Cough
$hortuss ofbre*th
Nose bleed
lmpai:red wound healing
tloar$snsss
Stuffy nose
Itching
Skin raslr
[Iivc*
Fonnntion of a blood clot that plugs the blood vesseh blood clots m*y break loo$e and travel to
another plece, such as the lung
Rare bqt Seriouql
r Damage of or clou in small blood vessels in rhe kidney thet ctrn ceuse complioations, sttnte of
which are serious including abnonnal destruetion of red blood cells (hemotysis) or platelets (that
help to clot blood) and kidney hilure
. Collection 6f signs and symptrrms th*t intlicate sutklen heart disea*e in which the heafi does not
get enough oxygen. Sudden symptoms such as chest pain. shortness of breath- or t-ainting could
inrJicate heafi disoase aucl should be rupoltrll riglrt away. liigns suclr as ut:rttonnul HKC arrd lrlood tests
can eonfirn: damage to the heart.
Heart failure : inability of trhe lreart t0 adequstely pump bloocl to supply oxygen to the body
Decrease in heafl's abili$ ts pump bloo<l during the "astive" phnse of the heartbent (systole)
I"Ieart attaok cause by a blackage or decreascd blood supply to the hs&rt
Inegular heartbeat resulting from an afrrormaliry in the one of tlre lower chambers of ths h6art (r'entricle)
Venticular librillation: irrcgular heartbeat that involves the low*r chamLrers ol'the heart {ventricles) that
results in uncoeirdinate<I cnnlraction ol:tlre heart; life threalening ancl potentially fatal, ncedirtg inrmediale
fistula: Abnormal hr:le bellr/eerl an orgall of tlro digestive tract attd attotlrer orgfrn or
a
1)
t
a
t
*ttention
. 
Castrointestinul
tissue
r 
(iastrointestin*l perforation : A tear or lrole in the stomach (}r gut lhat cnlt le*cl to serious cornPlications
and mry require $urgerY to rcPatr
. 
Sore (ulcer) somcwhsrs in tle digestive trect
. 
Serious, lifs+lrreatening allergic ieaction requiring irttmediate medisal trealrnsnt by your dostor' The
reactiorl nray inrlude eKtremely low lrlood pi*.ur*, srvelling of the throut' cliff iculry brenthittg, and loss of
consciousnes*.
r Leakage from stomach due to breakdown of an anastomeisis {strrgical conneclion of two separate body
strurturss)
Bleedirrg in lhe brain
0t I 7 2011
*l'16
Atjfi 1 ? u011


Titg of $tudy: A phase ll'liial eif Doxil , Carboplatin nnd 8ev*eieumtb in'lriplu Negulive Previously ljntrcatal Mr*nstrtic Breast
r 
Stroke caused by decroosed blood flow ts tlle brain
r 
Abnormal chaflse$ in tlre hrain th*t can c&us6 s collection of symptoms including hcadacho, confusion'
**irur*u, md vifion loss associotsd with MRI inuging findings (RPLS)
r 
A condition in which the kidneys leak a targe alnount of protein into the urine th*l can cau$e
complications inclutling swelling and kidney lailure
' 
Kidney failurc
r 
Abnormal hole tretween part of the urinary systenl and anotlrer or&atl or ll$sue
r 
Abnormal hole betrveen the vagina snd another organ or iis$ue
r Abnormal hole betwpen the lower breathing tube *nd the boely cevity &at surrounds the lungs
r 
Bleeding from the lungs
. 
Hole in the wall that separater the noskils of the nffie
r 
Abnormal hale betwsen the bretthing tube (windpipe) end the lube th8{ gors liom mouth to stomach
through which food pa$res (e.*ophagus). Thi* is life-lhreattr:ing and patentially fhtal'
r 
Blockag* o, n*rro*ing erf a h1:od wssel (artery) rhat c{n cause danrage or loss of futtctiotr including a
heart attack or stroke
The following rro cide sfrecB, which may happen with th* rlrug &pirubicin:
tikely:* Rddish urin{for
. Nausee
. Yorniting
. Mouth sores
r Dehydr*tion
. Diarrh*n
l-2 dsys)
. 
Signs ofcongestive heart fuilure {e.g., shortness cflhreath, ankle swolling)
r Fevsr
. $igns of infection
r Pnin, burning or stinging at the injection site
, Rever$ible aloPecia {hair loss)
. Low blood c*ti "ounL 
(anemia,leukopenia, neutropenia, and thrombocytopnia)
. Fatigue
r Temporary or permanent loss of men*trual cycle in womsn
r Hot flsshes
r Rash/itch
Rarr b*t $prious;
Epinrbicin causes *everal side effecrs, $ome of which can tre $evere. ln somc c8ses' epiruu'icin may need
to be stopped beoausc ofthese side efF€ets.
One of the most darrgerous ride effects of epirutricin i.s hetrt darnage' hr its most sevare form, this heart
tlamagc manifests as congestive heart fhilure, rvhich can be futsl. Heart prublems can occur tnonths or
y.urr-o{t*, slgpping epirubicirr. The prabaiilit,v ot'developing hcart failure is dependsnt on ths
ffiffi;; ;;#;iU;ti;;r;*ni*u is thq rotai amou*t o{'epiiubicin given aftu all chcmotherapv
,,--r,ri,".-
NPPNOV* EXPIRES
irge l0 of 16


Ildr of lhdy: A phase ll ,l'rial of lloxil - carboplatin and Bev{xiiaumab in Triph N*gative Prcviously Untrented Meu${,lie Brtst
*ose of S50rug/m2 and less than 39{ after a cllmulativs close ol'900 mg/m2. The risk of corye$tivc heert
fbilure is a condition wher:s the heart does nut pump enough blood to support the nesds of the body.
$econdary Leukemia has also been reportsd within three years of'stuppifig epirubicin' Based on several
studies, the risk ofsecondary leukenria has been estirnated at ?% nffer eight years. Secondary leukemia is
o cancer of the white blood cells in your bloocl thut fight irrtbctions that might be caured by treatrnent
with epirubioin.
gthqr risk$ $ssocitted lvith the studYr
, In "ddifis; 
to the known side effects listcd for three mcdirines ur*d in thix stutly' there ir slss
thc posribility of tr n$il or u$onticipcted *ide effect when the thrce mcdieinos srt aombined
together
r There is the risk that this treetment may nelt work frrr ynu.
. 
Side effests of having blood drawn liom a vein or lV {intravenous) t}rerapy: When your blood is
drawn, there is u po.*ibility that there may bc a bruisc ("black and blue" rnark), bleeding or intbction
(rarely) at the place where the needle entered yotr vein.
. Som. patients whu have an MRI moy dcvelop claustrophobia' lt is irnportant to let your doetor
know if you have this problem. If you have a pacemaker or otlrcr metal object or device in your
body or huo. rr*r worked with sheet metal you may not be able to have an MR[.
. 
Some of the te$ts that wilt be performed on you (X-rays, C'[ scans, MRl, and/or bone scans, and
MUGA scan [if requirert]) wilf expose you to cr:ntrolled amounts of radiation' The CT and/or MRI
scans and MTJCA u*** *ltt involve dyes being iniectcd into your vtin. l'here is a risk of allergic
reaction to the dye, 'I'he injection oi suL,stances such as dyes into your blood may c'ause pain,
srvelling, bruising, irritation or redness at the site" feel thint, or infbction at the site of the necdlc
pun*t r". 't-l.re collection of tumor tissue sdds no additional risk to you since this tumr:r tissue was
obtained frorn a preyicus biopsy. It is important that you report any side effbcts to your study dr:ctor
&s $oon as possible. You should nat wnit until your nexl scheduled visit.
Other Medicqtions or $ulrplqmentsr
Y"" -horld ,oftakearr},over ihe counter merlicines, herbal products, vitamins or I'rrod supplements ur
any other types of special products while participating in this slucly, unless you tell the study doctr:r and
permission is given to sontinus taking these meeiicines. 'I'here could be e1rug interactions with ths sver
ihe countsr products, not known at this timo, that could potentially harnr you. You shtluld also tell the
study doctor about any and all medicines other doctrrrs may have prescribed fur you to take.
Prssulncv and Childbssrins Precuqfioqs:
ft" d*gr irJhi55tutly may affect the w*y fl womnn's ovaries work ancl her ability tCI get pregnant. If
you arc 51 \iloman wlro is *hle to become pfirgnant and have a baby ancl are sexually active with men, yotl
must agree to not beeome prsgnant during the tirne you are taking part in this study hecause it is nr:t
known what ell'ects this trertment may have on a developing haby. lf yotr arc not willing to u$e
adequarc birth contr*l, you must not sign up for this study, Adequate birth cuntrol includes: abstinence,
a diaphragm with crcam to kill spenn cells, an intrauterine clevice (-'ltIn"), latex condoms. a tubal
lnril*uptives. You should contintle to use adequate birth
I 7 tctz
ligation (having
APPROVED
0ci ? tilfl
I'aro I I o{'lfr


.Iitlc of .studyl A pha*e ll liial of Drxil , carboplatin llnd Bcvsciuumab in Triplu N*gative Previously untrtotcd h'lutauatie Breast
you must not breast feed a b*by rvbile taking part in this study und for 3 months after stopping ths
study, b*cause the effects of this treatment nn a baby cannot be determined'
lf you have any questions about birth congol, please spe*k to your study doetor' If you become
pregnant, you *o*t immediately tell the study doctor, and you will stop stucly therapy'
Are there any benefits if I chogse to participate in this resenreh *tudy?
The benefit* of p"*i*ipnting in this stu<iy *uy b* thnt your cfllcer may shrink or stay the same sizs for a
long period oftinre. l{owever, you mey r*c*iu" no clirect benelit tiom taking part in this study'
ltrhrt ore my $tern*tives if I don't wrnt to prrticip,ttt ln this *tudy?
yourfutor iswilling-io di**o*, the benefits and side.ff**t* of otherforms oftrsatmentsotherthamthis
study that are avail*ble. These includs:
r Other usual ehemtrtherupy for your type of cancer, rvhich may include tht same ffis of
chernotherapy that is used on this study.
r Otherexperimental studies with chemotherapy, hormones, radiation therapy, or new anti*cancer
agent$ may be available for your disease.
r you may also choose ns furthsr tre&tment, with care and mediqines to help you lbel more
c.omfortsble.
please feel free to discuss these other options with your doctor and ask [lny questions you may have'
Take as mueh time tl$ you nced to make your decision
How will I knorry if ther* ls inl'ormation Imrnod thnt might affcct rny willingnese ta participate in
this rcrerrch rtudy?
During the course pf the sudy you rvill he updated abnut any new information that may affect your
willinlress to remain in the study. If new inlormation is learned that may aflbct you afterthe study has
completed, you will be contacted.
who will have access to my research recortls from thlr study?
By taking part in this study" you should understand that we will be cr:ltecting yow personal health
inforrnation. This inoludes. but is ncrt limited to, ttenrographic elata (your name, date of birth, etc') ftnd
clata on your healrh (your history, physical findings, laboratory resutts, study-related lindings, etc')'
Duri,g tir* .ouru* of iiris triat, stidy visitors (known as monitors) will revierv yuur nledical and rese*rch
re*ord to make sure \&'e sollected your sturly information properly. These tnonitors are empl<lyed by The
Cancer Institute of New Jersey. Sonretinms, they lvill *eed to take notLls or photCIcopy parls of your
megical record. We will replaee your nan"le on these pagss with yuur assigned sttrdy nurnb$r' "l'his data
wiil he reported to other staff at 'I'he Cancer lnstitute nf New Jersey on a regular basis, ns required by
the stldy, The Cancer Institute ofNew Jerscy will an*lyzc! pnlcess. and storE your dota with electronic
data processing systems" The authorizati$n ftr use of yortr research data has no expiratinn date' Your
AUO 1 ? TOI?
)$rre:09i l2ll I
therapy,
l? o1'l{"r


Titlu of $tudy: A Phase Il 
.l risl ol, tkxll , Carhoplntin und $evuci?urnab in 'l'riple Negatiue Prcviously Unlreat*d Mctests{ic 8re8st
persoilal hedth infnrmation m&y be subjectredisclosin.c lry
i,.Iu*unResearchServicesandifitisr,eelisclosed,itmayn0@ipersonalidentity,
however, that is ygffi ngme, ucllress and other idenri{iers will remain cnnfidential (a stutly nurnher will
be used for your name), Only the study doetor, research team arrd study monitor will be able to link the
study number to your nflrne . Your tlata nray also be foruarded to domestic and foreign drug regulatory
agencies if you have an adverse (bael) reacticln.
The f.ollowing group$ of people nray also be allowed to inspcct sections r:f your medical and research
records related to this studY:
a
a
I
a
a
a
a
a
your intbrmation may also be subrnitted to domestic (within the United States) and lbreign drug
regulatory agencies in applications ibr nrzu'kvting authori:r.ation arrd nray be used in scientific
p,iUti".tlons fjournals. articlcs). If the iindings fiorn the study are publi*hed. you will not be identified
Ly nu**. your itlentity will remain eonfidcntial unless thc larv requires us to give out this in{brmation,
such as in the case r:l'r'ep*rling pcople wlto havc cliseascs otltcr; r;an catuh, ll this ctlli$, you will be
infornred of the inlent tn di
tion to the authodzed state agency. Such a law
has already existed in
you have the right to look at your per*onal infonnation at your study doctor's oflice end tu rcquest any
conectiom of your personnl datg thst are wrong.
Ifyou {o not cign this approval furmn you will nct be able to take part in this rEsearch stutly'
lVill therc be nny cos(s ttt me to participntc in this studyl
The drug Bevacizumab will be supplied ut n$ cotit to yuu
your health insurance caricr nr rhird party payer will bc billed f-or the c.ost of rautine blood tests, x-
Hrys, sgans and other routine tcsts thal would be part of your stttltdard rnedical care even ifyOu were not
t*ting part in this study. Whale'i,er cosls yorr insurnnce cornp&ny does neit pay will be your
,*.poir*lbility. All cloctcri's or hospital cr"rsts will bc ch*rged tc you iu tltc same lvay as if you rvere not
APPROVAL EXPIRT$
part clf this study.
ll ul' 16


Title of srudy; A fhuse Il rrial of Dcxil , tturboplnrin und Bevacizumab in Tripk Nrgulive llrrviuusly untrtfitd Mrtnstutir: Ilreasl
Will I be paid to pnrticipat* in thie study?
you will not be paid or receive any CIther forn of ccnrpen$etion to taks pert in this study'
Whot will hrppen if I become injured during the sltrdy?
If you participare in this stutly, youivill be cxpr:scrt tei certain risks ofphysical injury in addition to thr:se
x*;;x*mi;;'.Hm:lffi ffi ;;[;;,ilf r;Tffi1'ilJ::l'l,i"ffit;ii'::$:;
as a direct con$equenc* orpa?i*ip*iiilTli,i* risearch. Your health insursnce carrier or other third
party payor wilt be billetl for the cost of this treatment. No additional financial payment is available'
you ure not giving up any of your legal rights by signing llris fomr or by participating in this research
study.
ill not provide paynrent for any nredical €xpense$, which you nray incur as a result of
y 
n in this studY.
What wig hlppen if I do not wish to p*rtiripate or dccide not to rontinue in the study?
you may choose not to be in the study and if you clo choose toparticipate it is voluntnry' You may also
ref,use to participate, or change your mind nt any time. lf you do not want lo snter thc study or decide to
withdraw(stopiaking part) iron: the stncly, your relaticnship with the stucly staff will not change, and
yo* may ct, ,o *itlJui penalty or loss ofbenefits to which you are otherwise entitled' lf ytlu do not
w*nt us to conlinue usi
already collested about you, you must withdraw your
permission in writing
Even if you withclraw our permission to use the data about
you. we cannotretrieve
ffi?fur* infomiation previously submitted. We are required by the
'pooA 
and Drug Administration however, to rontinue to report anything that relates to the safety of these
drugs
At any tims, the stutly doctur can decicle to withdraw you fiorn this study because tu take pan Further
wouli not be in your best interesl. Your study cloctor cen stop trealment even if you are rvilling to
continue. If you, or your study doctor, dccidc to rvithdraw you from the study you may be asked to
retum fbr a final visii fr:r salety rca$ons.
Also, you should unders{and fhat the stucly doc.tor can withdraw you {ium thc study at any tim* ifyou dc
nst fuilow the instructions related ta the study, or if you need a different treatment.
Who may I eontsci if I hsvt any que$tions?
If you have any que$tion$ about your pcrticipation in this .sludy" ysu can oontact the ntudy doctor:
a research suhiect,,YoLl can conlact:
IItl| fr i12200702?4
Version D$le: 09/l?J'l I
If you have any quc$tioils about your rights as
Pase 14 $l'I
1 ? ?0r?


.lirl* of study:A phrse ll Trial 0f Doxil , carboplarin rnd s*v*cirumab in'tr'riple Negntivr Pruviously untrcuted Mcttstatic Brcast
ASDITIONAL RASEARCI{ TBSTING, }'UTURN USB TISSUA SAMPLSS ORTHE IHTENT
T0 $T0nm $AMfI,E$:
Pleasc initial each one of the following sentsnces that applies:
I agfee to be contacted by the tnvestigators tu*r firture research studies.
I do not agree to be contactect by the Investigators fbr future research studies.
I agrec to tha use CIf my bloo#tissue fur future roseffch
,I do not agre t0 the use of rny bloodliissue for future resealch
I understand that if I do not v{ant my sarnp}es used for future research it will not aflect my ability to
take part in this study or in future studies.
lryhat &r$ ury right* if I dccirle to pnrtieipato in this re*sareh *tudy?
you have tle right to ask questions *on***ing any part of the study at any time. You slrould not sign
this fomr unless you have had a chance to ask que*iions and receive &nswer$ to all of your questions'
I have reacl this sntire form, or it has been read to *re, and I believs that I understand what has been
discussed. All of rny questions regnrdiug this form or this study have been answeretl. I agree to
perticipate in &is researsh study and have been given a copy of this consent'
Patient Name:
Patient Signature:
I)ntc:
SIGNATURN OT REANER/TRAN$LA"TORIS HT{ PATIINT DONS NOT REA"D ENGLISH
English well. I read"English *ell;nd arn flus,tt in . - ,.*. :*.: ,. , I language the patient
understands well. I understand the content of this *onse* filnn and hnve translatsd for the patient the
entire content of this forrn, 'l'o thc best of niy knowlcrlge, the patient undcrst*nds the content of this
forur and has hacl un opf$rtunity to nsk questiuns reganling lhe consent lbml and thu sludy, and these
questions have been answered.
APPROVEO
0rT ? 20ll
Ilage l5 ol'f 6


Title of Snuly: A Ph$se II Triul of Soxil , Curbnplutin llnd lleyminumah in Triplu N*gmiv* Pruvitusly l-htreated h{qtastatic l]rcnst
Canc.er
Rsoderl
Translator:
Witness:
Nuuc:
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Dute:
Signature :
$IGNATURS O$' INV USTI GA'I'OR OIT RNSPONSItsLN INDIVIDU AL
To the best ol my ability, I have explained anil discussed the full contents oi'the study including all of
the infurrnation containe$ in this consent t-orm. All qutstions of the patient have been eccurately
answered
Narne of Ir
$ignature:
and the patient h*s been given a copy ofthe consent.
nvestri gaiorlPersott Obtai ning Cunsent :
ffi61sn
0[T ? 2011
Datc:
Duie:
AUG I 7 t8t2
Pag* l(r ol' ltr

Prot_000.pdf: 
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 
Date: 10/17/13
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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
\rersion Date: 10/l 7/13
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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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