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 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
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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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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
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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.
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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.
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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
$ainfirl erytherna.
ederua, or ulcers. and
cannot eat)
Delny dosing up to 2 rveeks or until resolved to Grade 0-1.
Decrease Doxil@ dose by 2Ao/o. Maintain the Carboplatiu close. If
afrer 2 r,veelcs ttrerc is no resolution, patient will be reruovecl from
thejtudy.
4
(requires parenteral or
enteral support)
Delay dosing up fo 2 rveeks or uatil resolved to Grade 0-1.
Decrease dose Doxil8 hy ZO%. Maintain the Carboplatin dose.If
after 2 weeks fhere is no resolution, patient rvill be rernovecl frour
{e study
7.4.3 Bevacizumab
There are flo tedrrctions in flre bevacizrunab dose. If adverse events occru'that requir.e holding
bevaciztunab, the dose will rernaiu the saure once treatment rcsuues.
Atty toxicify associated or possibly associated rvith bevacianmab treatment should be
managed according to standard rnedical practice. Bevacizurnab has a terminal half-life of 2 to
3 weeks, therefore, its discorrtiutmtion results in slow elimination over several rnonths. There
is no available antidote for bevaciaunab.
Patients should be assessed clirrically for toxicity prior to, dtuing, and after each fufrision. If
urunanageable toxicity occuls because of bevacizuurab at aoy time during the shrdy,
freatment with bevacizumab should be discontinued llowever, patients may continue with
doxil or epirubiciu ald Carboplatin h'eatment if admiuistration criteria are rnet.
Adverse events requiring delays or pernarlent discontimmtion of bevaciztuuab ale listed in
Table 7.4.3.
Regafdless of the reason for holding study dnrg b'eatrnent, the maxinrum allowable length of
treatneut internrption is 2 months.
Version Date: 1O/17i13
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A Phase II Trial of Doxil . Carboplatin zuld Ber,'aciamab in Triple Negative Preliogsly Urtreated Metastatic Breast ca,cer
1 .4.3.1 Infusion Reaction
hrfusion of bevaciztunab should be interrupted for patieuts who develop dyspnea or clinically
sigificant h1'pote$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
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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$ter patients will have study treatrnent held turtil all of the following
cntena ale il]et:
o The bleeding has resolved and hemoglobin is stable.
o There is no bleeding diathesis that would increase the risk of
therapy.
o Theie is no auatomig or pathologic condition that significantly
iucreases the risk ofhernorrhage reculrence.
Patients who experience a repeat Grade 3 hemon:hagic event lvill be
discontinued fiom receiving -bevacizuurab.
Discontinue bevacizuuab.
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A Phase II Trial of Doxil . Carboplatin and Ber.aciaunab in Triple Negative Previously Unseated Metastatic Breast Catrcer
Table 7.4.3 Bevacizumab Dose Management due to Ath'erse Events (continued)
Yenous Thrombosis
[Note: Patients rvith lung carcer placed on anticoagulant therapy for a thrornbotic event should be
discontiuued froru receiving bevaciztrmab]
No dose ruodifications for Grade l/2 events
Grade 3/ Asyrnptomatic Grade 4
Hold stttdy dnrg heatureut. If the plarured dumtion of ftlll-dose
anticoagrdation is <2 weeks, sfudy dnrg should be held rurtil the flrll-dose
anticoagulation period is over. If the plarured drration of full-dose
anticoagulation is )2 weeks, silrdy drug maybe lesuned during the
periotl of firll-dose anticoap5ulation if all of the following criteria are ulet:
. The patient mrut have an in-rauge INR (usually between 2 and
3) on a stable dose of warfariu (or other anticoagulant) prior to
restarting study dnrg treaturen{.
e The patient must not lnve had a Gmde 3 or 4 hemon'hagic
event while on anticoagnlation.
r The patient rnust not have had evideuce of tumor involviug
major blood vessels on any prior CT scan.
Discontinue bevaciauuab.
Syntptomatic Grade 4
A$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
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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.
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%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-