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

Official Title:
A Phase 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.
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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
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A phase II Trial of Doxil , Carboplatin and Bevaciarnab in Triple Negatil'e Prelior$ly Untrealed Metastatic Breast Caocer
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A phase II Trial of Doxil , Carboplntin and Bevacianurab in Triple Negative Pret'iouslyUrltreated Metastatic Breast Cancer
53. O'Brien M, Wigler N. Iubar M, et al: Reduced cardiotoxicity and compamble effrc.acy in a
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A Phase II Trial of Doxil . Carboplath zurd Ber.acianflrab in Triple Negative Previo[sly Utlteated l{etastatic Breast Cancer
Appendix A
Performance Status Criteria
f,COG Performance Status Scale
Karnofsky Performance Scale
Grade
Desuiptiorrs
Percent
Descriptiol
0
Nonual activity. Fully active. able to
carry on all pre-di*ase perfotnrance
uithout restrictiorr
100
Nomral. uo courplaiuts, no evidence of
disease.
90
Able lo carry oD nonnal actil'ity: minor
silns or symptolrs of disease.
1
Synrptorus, but arubulatory. Reslricted
in physically steuuors activity, but
ambulatory and able to cany ottt work
of a light or salerrtary natue (e.g..
light houseu,or*. office uork).
80
Nornal activirywith effort some sigrx or
syrup{otus of disease.
70
Cales for self, turable to carry ol nornral
activity or to do active wolk.
2
In bed <507o of the tiure. Alrbulatory
and capable of all self+are, Intt urable
to cany out any r,r'ork actirities. Up
and about nrore than 50% ofuaking
hours.
60
Requires occasional assistauce, but is able
to care for urosl of hiy'lrer needs.
50
Rsquires cousiderable assistalce and
&eouert medical care.
3
lnbed >500/o of the tilre. Capable of
only limited self-care. cotfiaed to bed
or clnir tnore than 50?6 of waking
hours.
40
Disabted, tequircs special care and
assistagce.
_t0
Ser,erely disabled. hospitalization
ildicated. Death uot irtmineut.
4
100% bedddden. Courpletely
disabled. Carurot ciury on any self-
care. Totally confiled to bed or chair.
20
Very sick. hospitalization indicated
Death not inurriuent.
l0
Moribuud, fatat processes progtre$smg
rapidly.
5
Dead.
0
Dead.
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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
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