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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
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