BRIEFINGDOCUMENTFORNDA#21-661

SynopsisofClinicalComponent

Theefficacydatabaseconsistsoftwoclinicalstudies,RT-008andRT-009.RT-009wasaphase

3,randomized,open-label,comparativestudyin538patientsreceivingastandard2-weekcourse

ofwholebrainradiationtherapyforbrainmetastases,30Gyfractionsperday,withsupplemental

oxygen,withorwithoutRSR13.Therewasnostatisticallysignificantdifferenceintheprimary

endpointofoverallsurvivalwhenanalyzedusingthelog-ranktest,mediansurvivaltime4.47

monthsinthecontrolarmvs.5.26monthsintheRSR13arm,p-0.169.Therewasalsono

statisticallysignificantdifferencesinthesecondaryendpointsoftimetoradiographictumor

progressioninthebrain,timetoclinicaltumorprogressioninthebrain,responserateinthebrain,

causeofdeathandqualityoflife.Thesponsorisrequestingapprovalbasedonthefindingofa

survivaladvantagewithRSR13+wholebrainradiationtherapy/supp1ementaloxygenvs.

WBRT/O2aloneinanon-prespecifiedsubgroupofbreastcancerpatientswithbrainmetastases.

Bysubsetanalysis,theobservedmediansurvivaltimeforbreastcancerpatientsinthecontrol

armwas4.57monthscomparedto8.67monthsfortheRSR13arm(p-0.0061,log-rank).The

sponsoralsodescribedaresponserateinthebraininthisnon-prespecifiedbreastcancer

subgroup,49.1%inthecontrolarmvs.71.7%intheRSR13arm.

RT-008wasasingle-arm,multicenterphase2studyinpatientsreceivingaconventional2-week

courseofcranialradiationtherapywithRSR13forbrainmetastases.Sixty-ninepatients

participatedinthisstudy.Thestatedobjectivesincludedresponserateinthebrain,median

survival,andtimetoprogression.Inthesettingofasinglearmstudy,itisdifficulttointerpret

timetoeventendpointssuchassurvivalandtimetoprogression.

TheMedicalReviewerhasthefollowingconcernsregardingthepivotalPhase3study:

1.Therewasnostatisticallysignificantdifferenceinsurvivalbetweenthetwostudyarmsof

RT-009intheintenttotreatpopulation.

2.Thesponsor'sfindingofasurvivaldifferencebetweenthetwostudyarmsofRT-009inthe

breastcancersubgrouprepresentsanon-prespecifiedsubgroupanalysiswhichshouldbe

consideredexploratory.

3.ThemarginalfindingsregardingresponserateinthebraininRT-009cannotbeconsidered

reasonablylikelytopredictclinicalbenefitsincetumorshrinkagecouldbeattributedtoradiation

therapygiveninbothtreatmentarms.Anotherfactorintheuncertaintyofthisfindingisthat

mostdeathswereattributedtonon-neurologicalorindistinguishablecauses.Otherconcerns

regardingtheassessmentofresponseinRT-009includethefollowing:

?Confirmatoryscanswerenotrequired.

?ThedesignationofCR/PRwasgivenwhetherornotanewbrainparenchymallesionwas

documentedonaparticularevaluation.Seebriefingdocumentforotherconcerns.

SeeSectionIVofthisbriefingdocumentforthesafetyanalyses,whichwillbepresentedinmore

detailattheAdvisoryCommitteemeeting.

TABLEOFCONTENTSFORBRIEFINGDOCUMENT

I.IntroductionandBackgroundP.3

ILDescriptionofClinicalDataandSourcesP-8

III.EfficacyP-10

ProtocolReview(RT-009)

TrialResults

EfficacyResults-Sponsor'sAnalysis

EfficacyResults-FDAAnalysis

ProtocolReview(RT-008)

TrialResults

EfficacyResults-Sponsor'sAnalysis

EfficacyResults-FDAAnalysis

IV.ReviewofSafetyP-61

A.Introduction

B.Exposure

C.AdverseEvents

ClinicalReview

I.IntroductionandBackground

A.DrugEstablishedandProposedTradeName,DrugClass,Sponsor's

ProposedIndication(s)9Dose,Regimens,AgeGroups

GenericName:EfaproxiralSodium

ProposedTradeName:Excelar

EstablishedTradeName:RSR-13

ChemicalName:2-[4-[2-(3,5-dimethylphenyl)amino]-2-

oxoethyl]phenoxy]-2-methyl-propanoicacid

monosodiumsalt

PharmacologicCategory:Radiation-sensitizingagent

DrugClass:Syntheticallostericmodifierofhemoglobin

RouteofAdministration:Intravenous

DoseandRegimen:75or100mg/kgdailyover30minutesthrougha

centralvenouscatheter,MondaythroughFriday,for

2weeks.Concurrentsupplementaloxygenisalso

administeredatarateof4L/minvianasalcannula

orfacemaskbeginning5minutespriortoinitiation

ofinfusion,duringinfusionandwholebrain

radiationtherapy(WBRT),andforatleast15

minutesaftercompletionofdailyWBRT.WBRT

mustbeadministeredwithin30minutesoftheend

oftheExcelarinfusion.

PopulationStudied:Patientswithbrainmetastasesoriginatingfrom

histologicallyconfirmedsolidprimary

malignancies,excludingsmallcellcarcinoma,

lymphoma,andgermcelltumors.

ProposedIndication:Adjunctivetherapytowholebrainradiationtherapy

forthetreatmentofbrainmetastasesoriginating

frombreastcancer.

B.StateofArmamentariumforIndication

Approximatelyone-thirdtoonehalfofalladultbraintumorsresultfromhematogenous

disseminationofmalignantcellsfromanextracranialsourcetothecentralnervoussystem.The

mostcommonsitesoforiginarethelung,breast,ormelanomaskincancers.Themedian

survivalfollowingtreatmentisonly3-6monthswhenmultiplemetastaticlesionsarepresent

andabout12monthsforthosewithasolitarymetastaticdeposit/1)Thecontrast-enhancedMRI

isconsideredthebestimagingstudytodiagnosebrainmetastasesandwillguidethechoiceof

management.TherearenoFDAapproveddrugsforthetreatmentofmetastatictumorstothe

brain.Acceptedtreatmentstandardsconsistofsurgicalresectionfollowedbypost-operative

radiationtherapy,wholebrainradiationtherapy(WBRT)alone,stereotacticradiosurgery,

interstitialbrachytherapy,andanecdotalreportswithhonnonaltherapyincasesofbreastcancers

responsivetohormones.Theuseofchemotherapyhasbeendisappointing.Corticosteroidsaid

inalleviatingperitumoraledema.Thepresenceofseizureactivityinpatientswithbrain

metastasesleadstotreatmentwithanticonvulsanttherapy.Venousthromboembolicdiseasealso

occursatahigherfrequencyinpatientswithbrainmetastases,oftenrequiringinferiorvenacaval

filtersorstandardanticoagulation.(2)

Corticosteroidswerefirstusedin1957inpatientswithbrainmetastasesoriginatingfromthe

breast,followedbydexamethasonein1961.Dexamethasonehaslessmineralocorticoidactivity

andhasbeenincludedinthestandardtreatmenteversince.Itsmainmechanismofactionisto

reducethepermeabilityoftumorcapillaries.(2)

Primaryradiationtherapyhasbeenthemainstayoftreatingmetastatictumordepositsinthebrain

for40years.Themediansurvivalofpatientswithbrainmetastasistreatedwithsteroidsaloneor

noformoftreatmentis1to2months.Conventionalwholebrainradiationtherapy(WBRT)

increasesthemediansurvivalto3-6months.Thereisnoconsensusontheoptimalirradiation

scheduleforpatientswithbrainmetastasis.Typicalirradiationtreatmentschedulesconsistof

totaldosesof30-50Gyin1.5-4Gy/dailyfraction,usually30Gyin10fractionsover2weeks.

Occasionally,reirradiationisemployedatthetimeofbrainrecurrenceinpatientswithpreviously

controlledsystemicsymptoms.(2)

ThreerandomizedprospectivestudieshaveevaluatedtheroleofsurgeryasanadjuncttoWBRT

forpatientswithasinglebrainmetastasis.Patchelletal.randomized48patientstoreceive

biopsyfollowedbyWBRT(36Gyin12fractions)orsurgicalresectionfollowedbyWBRT.(3)

PatientstreatedwithsurgeryfollowedbyWBRThadfewerlocalrecurrences(20%vs.52%,

p<0.02),improvedsurvival(40weeksvs.15weeks),andhadabetterqualityoflifeasmeasured

bytheKarnofskyPerformanceScale.Vechtetal.alsorandomizedpatientstoWBRTaloneor

surgicalresectionfollowedbyWBRTandshowedabenefitinthetreatmentarmconsistingof

surgeryfollowedbyWBRT.(4)However,nobiopsywasperformedtoconfirmthepresenceof

metastaticdiseasetothebrainandtheradiationusedwasanunconventionalschemeusing40Gy

over2weeks.Conversely,Mintzetal.observednodifferenceinsurvivalorqualityoflife

betweenpatientswhounderwentsurgeryplusradiotherapyandthosehavingradiotherapy

alone.(5)Theresultsfromthe43patientsrandomizedinthatstudymaynotbetruly

representativegiventheirlowerbaselinemedianKarnofskyPerformanceStatus(KPS)and

higherproportionofextracranialdisease.

Stereotacticradiosurgeryisusuallyreservedforsmall(<3cm)lesions.Itisperformedusing

highenergyroentgenogramsproducedbythelinearaccelerator,gammaraysfromagamma

knife,orwithchargedparticlesproducedbyacyclotron.Theuseofthismodalityresultsina

higherconcentrateddeliveryofradiationtothetargetedvolumeandlessradiationexposureto

normalnon-targettissue.(2)

Interstitialbrachytherapyisusuallyperformedatthetimeofsurgicalresectionwithimplantation

ofradioactivenuclidesintothewallofthesurgicalcavitytodeliveranadditionaldoseof

radiationtherapytothetumorwhilelimitingtheirradiationtothesurroundingbrain.Although

interstitialbrachytherapyisrarelyperformedforsmalllesionssuitableforradiosurgery,itmay

havealimitedroleformetastasestoolargeforradiosurgery.(2)

Thereisnowevidencethattheblood-brainbarrierispartiallydisruptedwithinabraintumor.As

such,theconceptoftheinabilityofchemotherapytoenterthecentralnervoussystemhasbeen

challenged.Otherfactorsmaybecontributingtothedisappointingresultsofchemotherapysuch

asintrinsicresistancetochemotherapyofmanytumorsthatmetastasizetothebrain.(2)

Inpatientswithhormone-responsivetumors,suchasbreastcancer,thereareanecdotalreportsof

brainmetastasesrespondingtohormonalagents,suchastamoxifenandmegestrolacetate.(2)

RSR13isasyntheticallostericmodifierofhemoglobin(SAM),promotingthereleaseofoxygen

totissue,oftenreferredtoasa“rightshift“ofthehemoglobin-oxygendissociationcurve.The

goalofadjunctiveRSR13therapyincancerpatientswithbrainmetastasesistoincreasetumor

oxygenconcentrationsinanefforttomaximizethecytotoxicityofradiationtherapy.APhase2

study(N=69)wasperformedtoevaluatemediansurvivaltime,responserate,andtimetotumor

progressioninpatientswithbrainmetastasesreceivingRSR13.AlargerPhase3study

(N=538)testedthehypothesisthatRSR13willimprovesurvival.Thesetwoefficacystudies

arethefocusofthisreview.ThesponsorisalsoconductingrandomizedphaseIIIstudiesusing

RSR13+WBRT/O2vs.WBRT/O2inpatientswithbrainmetastasesoriginatingfrombreast

cancerandNSCLC.

C.ImportantMilestonesinProductDevelopment

ClinicaldevelopmentofRSR13commencedinJuly1995.RSR13hasbeenstudiedin18

differentPhase1throughPhase3clinicaltrialsunderthreedifferentINDs.Twelveclinicaltrials

ofRSR13havebeenconductedunderIND48,171.DuringthedevelopmentofRSR13,studies

havebeenconductedunder2additionalINDs:IND52,999(DivisionofCardio-RenalDrug

Products)forthepreventionortreatmentofmyocardialhypoxiaandIND53,874(Divisionof

Anesthetic,CriticalCare,andAddictionDrugProducts)forthepreventionofhypoxiaassociated

withsurgery.

RegulatoryHistory

June13,1995:IND48,171wassubmittedtotheFDA.

November30,1999:AnEndofPhaseIIMeetingwasheldtodiscussFastTrackdesignationand

appropriateendpointsforfuturePhaseIIinvestigations.

October13,2000:FastTrackdesignationwasgranted.

February23,2001:AnEndofPhaseIImeetingwasheldtodiscussincreasingthenumberof

patientsenrolledinstudyRT-009toallowsecondaiyanalysisofsurvivalinthesubpopulationof

patientswithbrainmetastasesfornon-smallcelllungcancerandbreastcancer.

November29,2001:AnEndofPhaseIIMeetingwasheldtoagreeonsurvivalastheprimary

endpointforastudyinpatientswithnewlydiagnosednon-smallcelllungcancer.

August30,2002:SpecialProtocolAssessmentrequestedforstudyRT-013:APhase3

Randomized,Open-Label,ComparativeStudyofInductionChemotherapyFollowedbyThoracic

RadiationTherapywithSupplementalOxygen,withorwithoutRSR13(efaproxiral),inPatients

withLocallyAdvanced,Unresectable(StageIIIA/IIIB)Non-SmallCellLungCancer.

November12,2002:APre-NDAmeetingwasheldandplansweremadetosubmittheNDAas

arollingsubmission.

July16,2003:SpecialProtocolAssessmentrequestedforstudyRT-016:APhase3Randomized,

Open-Label,ComparativeStudyofStandardWholeBrainRadiationTherapywithSupplemental

Oxygen,withorwithoutConcurrentRSR13(efaproxiral),infemaleswithBrainMetastasesfrom

BreastCancer.

July25,2003:Pharmacology/ToxicologydatawassubmittedtotheFDAasthefirstcomponent

ofarollingNDA.

October1,2003:CMCdatawassubmittedtotheFDA.

December4,2003:ClinicalandStatisticaldataweresubmittedasthefinalcomponentofthis

NDA.

D.OtherRelevantInformation

RSR13isnotapprovedinanycountry.

II.DescriptionofClinicalDataandSources

A.OverallData

NDA21-661containstheprimarydatafromtwoefficacystudies,RT-008andRT-009,RT-009

wasconductedin40centersintheUnitedStates,inadditionto15inCanada,4inAustralia,4in

Hungary,3inBelgium,3inFrance,3inGermany,3inIsrael,3intheUnitedKingdom,2in

Italy,and2inSpain.Summaryinformationfrom538patientsenrolledintothisstudyfrom

2-16-00through9-24-02wasincludedinthissubmission.Rt-008wasconductedin16centersin

theUnitedStatesand1centerinCanada.Summaryinformationfrom69patientsenrolledfrom

2-24-98through5-28-99wasincludedinthissubmission.

B.DescriptionofClinicalTrialsRT-008andRT-009

Table1:ClinicalTrialsSubmittedtoNDA21-661

StudyIDDesignDose,RouteObjectiveNDurationTumorofPrimary

andOriginEndpoint

Regimen

RSR13Phase3,RSR13:100Efficacy,RSR132-weekBreast,Survival.

RT-009randomized,or75mg/kgSafety,and271entered.treatmentNSCLC,

open-label,centralIVPK'271analyzedphaseplusother

comparativeinfusionoverfora1month(melanoma,

30minutesefficacy/266fbllow-upGU,GI).

dailywithinanalyzedfbrevaluation.

30minutessafety.Patients

ofWBRTupwere

to10dosesCONTROL:followed

(plus267entered.fbra

supplemental267minimum

O2).analyzedfbrof6

CONTROL:efficacy/263months.

WBRT(plusanalyzedfbr

supplementalsafety

O2)w汕out

RSR13.

RSR13Phase2,RSR13:100Efficacy,69entered2-weekBreast,Survival.

RT-008nonrandomized,mg/kgwithSafety,and69analyzedtreatmentNSCLC,

open-labeldosePK/PDfbrefficacy/phaseplusother

reductionto69analyzeda1month(melanoma,

75and50fbrsafetyfbllow-upGU,GI).

mg/kgevaluation.

allowed,Patients

centralIVfollowed

infusionoveruntildeath.

30minutes

dailyjust

priorto

WBRTupto

10doses

(plus

supplemental

O2)

Derivedfromapplicanttable2.7.3.2.1(SummaryofClinicalEfficacy)

C.Post-marketingExperience

Thereisnopriorpost-marketingexperiencewiththisdrug.

D.LiteratureReview-Anextensiveliteraturereview,includingareviewofsome

ofthesourceslistedbelow,wasperformedbytheSponsor.

1.Shaw,EdwardG.,Bourland,J.D.,Marshall,Mark.CancersoftheCentralNervousSystem.In:

KahnF,PotishR,eds.TreatmentPlanninginRadiationOncology.Baltimore:Williamsand

Wilkins,1998:491-494.

2.WenPY,BlackPM,LoefflerJS.TreatmentofMetastaticCancer.In:DeVitaVT,HellmanS,

RosenbergSA,eds.Cancer:PrinciplesandPractices.6thEdition.Philidelphia:Lippincott,

WilliamsandWilkins,2001:2657-2667.

3.PatchellRA,TibbsPA,WalshJW,DempseyRJ,MaruyamaY,KryscioRJ,MarkesberyWR,

MacdonaldJS,YoungB.ARandomizedTrialofSurgeryintheTreatmentofSingleMetastases

totheBrain.NEJM,1990;322(8):494-500.

4.VechtCJ,Haaxma-ReicheEM,etal.TreatmentofSingleBrainMetastases:Radiotherapy

AloneorinCombinationwithNeurosurgery?AnnalsofNeurology1993;33(6):583-590.

5.MintzAP,KestleJ,RathboneMP,GasparL,HugenholtzH,FisherB,DuncanG,SkingleyP,

FosterG,LeVineM.ARandomizedTrialtoAssesstheEfficacyofSurgeryinAdditionto

RadiotherapyinPatientswithaSingleCerebralMetastasis.Cancer1996;78(7):1470-1476.

6.AkazawaK,NakamuraT,PaleschY.PowerofLogrankTestandCoxRegressionModelin

ClinicalTrialswithHeterogeneousSamples.StatisticsinMedicine1997;16:583-597.

7.GasparL,ScottC,RotmanM,AsbellS,PhillipsT,WassermanT,McKennaWG,ByhardtR.

RecursivePartitioningAnalysis(RPA)ofPrognosticFactorsinThreeRadiationTherapy

OncologyGroup(RTOG)BrainMetastasesTrials.Int.J.RadiationBiol.Phys.,1997;37(4):

745-751.

8.PorsH,EdlervonEybenF,SorensenOS,LarsenM.LongtermRemissionofMultipleBrain

MetastaseswithTamoxifen.JournalofNeuro-Oncology.1991;10:173-177.

9.GrayRobertJ.AClassofK-SampleTestsforComparingtheCumulativeIncidenceofa

CompetingRisk.TheAnnalsofStatistics.1988;16(3):1141-1154.

III.Efficacy

TheefficacyreviewisbasedprimarilyontwomulticentertrialsofRSR13entitled:

(1)RT-009:APhase3,randomized,Open-Label,ComparativeStudyofStandardWholeBrain

RadiationTherapywithSupplementalOxygen,WithorWithoutRSR13,inPatientsWithBrain

Metastases

(2)RT-008:APhase2StudyToEvaluatetheEfficacyandSafetyofRSR13Administeredto

PatientsReceivingStandardCranialRadiationTherapyforBrainMetastases

Below,theprotocolsforeachoftheseclinicaltrialsisreviewedindependently.

RT-009:

APHASE3,RANDOMIZED,OPEN-LABEL,COMPARATIVESTUDYOF

STANDARDWHOLEBRAINRADIATIONTHERAPYWITHSUPPLEMENTAL

OXYGEN,WITHORWITHOUTRSR13,INPATIENTSWITHBRAIN

METASTASES

PROTOCOLREVIEW

Table2.ProtocolMilestones(DerivedfromSponsor'sTable9.15,FinalStudyReport)

MilestoneDateComments

Firstpatientenrolled2/16/2000N/A

Amendment#13/2/2000StatedMRIpreferredoverCT.

PETaddedasanoptionfbrstaging.

DosingadjustmentGuidelinewas

changedtoincludetheinstruction"if

SpChwhilebreathingroomairon

anyRTday<90%,RSR13wasto

beomitted.^^Physicianjudgment

couldbeusedindeterminingclinical

significanceofanAEwithrespectto

omittingormodifyingtheRSR13

dose.

Amendment#26/05/01Samplesizeincreasedto538

patients.Enrollmentcompletion

extendedby6months.

Inadditiontosmallcelllungcancer,

extrapulmonarysmallcell

carcinomasexcludedfrom

enrollment.

Calciumchannelblockerswere

addedtothelistofmedicinesthat

couldpotentiateorpossiblyinteract

withRSR13.

Expandedwarningsaboutuseof

concomitantCCBsandACE

inhibitors.Asuggestionwasadded

tostartRSR13dosingat75mg/kgin

patientstakingtheseclassesof

antihypertensivemedications.An

additionalrecommendationfbr

patientswhohadaprevious

nephrectomytostartdosinga75

mg/kg,toadvisepatientstoavoid

smokingduringtheRSR13

resaturationperiod.TheDosing

AdjustmentGuidelinewasexpanded

toincludeweightandgender.The

scalefbrevaluationofhypoxemia

AEswasinitiated.

AnalysisoftheNSCLC/breast

populationwasincorporated.

Amendment#310/09/01Includedoptiontotreatbrain

metastaseswithCobalt60.Clarified

theconditionsunderwhich

concurrentRTcouldbegivento

extracranialsites.

DateofPrimaryAnalysis1/31/03N/A

(DataCutoffDate)

NDAsubmittedcompleted12/4/03N/A

Reviewercomments:TheSponsorstatedthatitwasnecessarytoenroll501patientsand

observe402deathstoclaimstatisticalsignificanceinmediansurvivaltimeandruleoutthenull

hypothesis.Totalenrollmentwaslaterincreasedto538patientsbasedonthepercentageof

patientsenrolledwithprimarycancersotherthanlungandbreast(samplesizecalculation

allowedthatif25%ofpatientsenrolledhad"other“primary,atotalof501patientswouldbe

enrolled.Ifotherprimarypatientsaccountedfor30%ofpatients,then538patientswouldbe

enrolled).

1.0Objectives

?TodeterminetheeffectofRSR13onprimaiyandsecondaryefficacyendpointsin

patientswithbrainmetastasesreceivingdailyintravenousdosesofRSR13administered

immediatelypriortostandardWBRT/supplementaloxygencomparedtopatients

receivingstandardWBRT/supplementaloxygen.

?TodeterminethesafetyofRSR13inthispatientpopulation.

?ToassessthepharmacokineticsofRSR13inthepatientcohortreceivingthestudydrug.

?Theprimaryefficacyendpointinthisstudywassurvivalinthetotalpopulation.A

secondaryanalysisoftheNSCLC/breastprimarytumorsubpopulationwasalsoplanned

withtheadditionofamendment#2.

?Secondaryefficacyvariablesweretimetoradiographictumorprogression,timeto

clinicaltumorprogressioninthebrain,responserateinthebrain,causeofdeath,and

qualityoflife.

1.1OverallSurvival

Theprimaryefficacyendpointwasoverallsurvivalusingthelog-rankstatisticunadjustedfor

covariates.Theprimaryfinalanalysesofthisstudywasundertakenwhentheplanned