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Introduc)ontoMedicalOncology
andClinicalTrials
ElizabethGriffiths,MD
AssistantProfessorofMedicineLeukemiaSec>on
RoswellParkCancerIns>tute
elizabeth. ri ths@roswell ark.or
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Outline
BurdenofDisease
ModesofTreatmentandSuccesses
MedicalOncology/HematologyTrainingandImplementa)on
DevelopmentalTherapeu)csandTes)ng
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Defini)onandBurdenofDisease
Oncology:Studyofmalignanttumorsoflethal
poten)al
Malignanciescanariseinany)ssue,atanyage
andspreadbydirectextensionorlympha)c/
vascularcircula)on
Canceristhe2ndleadingcauseofdeathinthe
USA(1/4USdeaths,3rdworldwide(aNerdz
andinfec)on
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2010Es)matedUSCancerCases
TOTAL 789,620(100% 739,940
(100%
Prostate 217,730(28% Breast 207,090(28%
Lung&Bronchus 116,750(15% 105,770(14%
Colon&Rectum 72,090(9% 70,480(10%Bladder 52,760(7% Uterine 43,470(6%
Melanoma 38,870(5% Thyroid 33,930(5%
HL 35,380(4% HL 30,160(4%
Kidney 35,370(4% Melanoma 29,260(4%
Oral/Pharynx 25,420(3% Kidney 22870(3%
Leukemia 24,690(3% Ovary 21,880(3%Pancreas 21,370(3% 21,770(3%
Other 149,190(19% 153,260(21%
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2010Es)matedUSCancerDeaths
AmericanCancerSociety,2010
TOTAL 299,200(100% 270,290
(100%
Lung&Bronchus 86,220(29% 71,080(26%
Prostate 32,050(11% Breast 39,840(15%
Colon&Rectum 26,580(9% 24,790(9%Pancreas 18,770(6% 18,030(7%
Liver/bileduct 12,720(4% Ovary 14,850(5%
Leukemia 12,660(4% HL 9,500(4%
Esophagus 11,650(4% Leukemia 9,180(3%
HL 10,710(4% Uterine 7,950(3%
Bladder 10,410(3% Liver/bileduct 6,190(2%Kidney 8,210(3% Brain/ervous 5,720(2%
Other 69,220(23% 63,160(23%
Mortality
153300/222520(69%
71890/424820(17%
51370/142570(36%18770/21770(88%
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Life)meCancerRiskAllSites 1in2 1in3
Prostate 1in6 Breast 1in8
Lung/Bronchus 1in13 1in16
Colon/Rectum 1in18 1in20
Uterus ----- 1in40
Bladder 1in27 1in84Melanoma 1in39 1in58
HL 1in45 1in53
Kidney 1in57 ------
Leukemia 1in67 ------
Ovary 1in72OralCavity 1in72 ------
Stomach 1in90 ------
Cervix ___ 1in145
Source:AmericanCancerSociety,2009
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CancerE)ology
Viral/Infec)ousMechanisms(worldwide#1
cause,HepB,HPV,EBV,HIV
Gene)cs
Chemicalcarcinogens(tobacco,benzeneetc
Environmental/IndustrialCarcinogens
Drug-inducedcancers(egsecondaryneoplasia
Radia)onexposure(
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Hepa>>sBandHepatocellularCarcinoma
ChenCJetal.JAMA.2006;295:65-73.
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CancerRate/100Kpopula;on
Gene)cSuscep)bili)es
BRCAMuta)onCarriersCanbegenespecificrisk,
orpopula)onspecificSPs
conferringenhancedrisk
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Smoking
Women
Men
WorldwideSmokingPrevalence(%
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HormoneReplacementTherapy
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GeographyandSunExposure
USA Australia
Site USA Australia
ALL 1in2 1in3
Prostate 1in6 1in5Lung/Bronchus 1in13 1in12
Colon/Rectum 1in18 1in10
Bladder 1in27 1in39
Melanoma 1in39 1in14
Stomach 1in90 1in55
sun
H.pylori
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DrugandRadia>onInducedCancers
AllanAMandTravisLB.NatureReviewsCancer2005;5:943-955.
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StrategiesinCancerManagement
PrimaryPreven>on- Tobacco,alcohol,dietarychanges,environmentalmanagement,vaccina5on,an5bio5cs
Screeningprograms(earlydetec>on/2
e
preven>on) Mammography,PSA/DRE,PapSmears,Colonoscopy
Treatment- Surgeryforlocalcontrol
Radia5onforloco-regionalmanagement
Oncologywhichincludescytotoxic,hormonal,immunological,targetedandsuppor5vetherapies
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WhatisMedicalOncology?
MedicalOncologist(Meh-dih-kulon-kha-lo-jist
Doctorwhospecializesindiagnosingandtrea)ng
cancerusingchemotherapy,hormonetherapyor
biologicaltherapy
ONenthemainhealthcareproviderforsomeonewith
Cancer
Providessuppor)vecareandcoordinatestreatmentbyotherspecialists
FromtheCIDic)onaryhp://www.cancer.gov/dic)onary/?expand=M
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MedicalOncologyTraining
MedicalSchool(4-8yrs
InternalMedicineResidency(3yrs
Oncology+/-HematologyFellowship(3-5yrs
PrivatePrac)ce Academics Industry
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RoleinCancerPreven)on
Recogni>onofsocial,occupa>onal,nutri>onal,sexualprac>cesthatcontributetoneoplasia
Educa>onofthegeneralpublicincancer
preven>on Smokingisthemostcommoncorrectableriskfactorforcancer(worldwidealsovaccina>onforHBV,HPV,preven>onofHIV)
Evaluateandscreenappropriatelypopula>onsatincreasedgene>ccancerrisk(BRCA,HNPCC,APC,p53,Rbfamilies)
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CancerDiagnosis
Requireshistologicproofonatleastoneoccasion
ewsymptomsinapa)entwithapriorhistory
ofcancerneedextensive/exhaus)veevalua)on
osymptomsshouldbeaributedtocancerwithoutbiopsyevidence,BUTcancershould
alwaysbeonthedifferen)al
Cancerpa)entscanalsohaveothersymptoma)cdiseases
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Chemotherapy
Chemicals(usuallygene-toxins,butnowmore
targetedtherapyaswellusedtotreator
controlcancer
Oncologistresponsibleforappropriatedrug
anddosecombina)on
Drug(suseddependoncancertype,stage,
pa)entageandcomorbidi)es
Managementofsideeffects
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PrinciplesofTreatment
Whereisthetumor?Whateffectdoesithave
onnormalorganstructure/func)on?
Howtoxicisthetreatmenttosurrounding/
systemicnormal)ssues
Istreatmentpoten)allyCURATIVE?Orisit
PALLIATIVE(decreasedsx,improvedQOL
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LawsofTherapeu)cs
I-ifitisworking,keepitup
Primumnonnocere-subjecttoconstantreassessment
inoncology.Cura5veandsub-cura5vestrategiesare
almostalwaystoxic,howmuchriskisworthit?II-Ifitisisnthelping,stopdoingit.
III-ifyoudontknowwhattodo,donothing.
Askyourcolleagues,gototumorboard.
IV-Thetreatmentshouldntbeworsethatthe
disease
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PrinciplesofChemotherapy
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Therapeu)cApproaches
Local/Regional
Surgery
Radia)on,PDT
Chemotherapy(egintravesical,intrathecal,topical,hepa)carterialchemoemboliza)on
Systemic
Chemotherapy(cytotoxic,hormonal,immunologic,tyrosinekinaseinhibitors
Suppor)veCare(an)-eme)cs,growthfactors,narco)cs
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CombinedTherapies
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eo-Adjuvant
Chemotherapyand/orradia)ongivenbefore
surgery
Ideaistoshrinkthetumortoallowsmaller
resec)onsororganpreserva)on(egforheadandneck,breast,pancreascancersorsarcomas
Responsetotreatmentgivesaninvivotestofchemosensi)vity/resistance(sarcomasandcan
provideprognos)cinforma)oninsomecases
Mayenhancetheefficacyofradia)onsoastoavoidtheneedforsurgery.
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AdjuvantTherapy
Post-SurgicalChemotherapyand/orRadia>on
GivenAFTERthesurgerytoimprovelocalcontrol,
decreaseriskofmetasta5cdiseaseandprolong
survival Canoffercureforsometumorswheresurgeryalone
hasalowcurerate(ieWilmsTumor,Osteosarcomas)
ProlongsdiseasefreeintervalforstageIIorIIIbreast
cancer,StageIIIovariancancersandStage(II)/IIIColon
Cancers,Pancrea5cCancersallstages,LungCancersIb,
II,IIIpostsurgery
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TargetedTherapies
medica>onswhichblockthegrowthofcancer
cellsbyinterferingwithspecificmoleculartargets
neededforcarcinogeneis/growth/metasteses,
ratherthanbygenotoxicstress Moreeffec>ve/lessharmfultonormalcells
NewParadigms-trialdesign,stabilityvsremission
MonoclonalAn5bodies TyrosineKinaseInhibitors
Vaccines
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UpfrontChemotherapy
Fordiseaseswhicharenottreatablewithlocal
measures
Formostsolidtumorsthegoalisusually
prolonga)onofsurvivalratherthancure systemicallyadministereddrugstoslowthe
growthoftumorcells,decreasetheburdenofmetasta)cdisease
BUT:SomeCancersarecurablewithChemotherapyalone
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CancersTreatable/Curablewith
AcuteLymphoblas>cLeukemia/Lymphomainchildren
Seminomas
HodgkinLymphoma ClassicalBurkiLeukemia/Lymphoma
Promyelocy>cLeukemia
DiffuselargeBcellLymphoma
HairyCellLeukemia
ChronicMyelogenousLeukemia
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CurablewithCombinedModality
on-Metasta)cCarcinomas
SomeearlyStagelungcancers
Headandneckcancers
EarlyStageGastricoresophagealcancers
BreastCancer(maybe
ProstateCancer(maybe
OvarianCancers(maybe
Sarcomas(some,aslongastheyaresmall
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WhatabouttheRest??
Boomline:
Metasta5ccancerisrarelycurable
Evencancerstreatedatearlystagesome5meshavemicrometastaseswhichshowuplater
CancersthatrelapseareoXendifficulttotreatduetoacquisi5onof
resistancetochemotherapy
SO:
Wetryhighdosetherapy(i.e.auto-transplantforbreastcancer)
Givegrowthfactorstotryandallowhigherdosesofchemo,morefrequently(DoseDensity)
Combinedifferentdrugsgivensequen5allytodecreasetoxicityandavoidresistance(PROmaceCYTABOM,CHOP,hyperCVAD)
Trynewdrugs/drugcombina5ons(CLINICALTRIALS)
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CancerDrugDevelopment
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Steps
ovelCompoundIden)fica)on(pre-clinical
Produc)onandFormula)on
Toxicologyevalua)oninvivo PhaseIClinicalTrials
PhaseIIClinicalTrials
PhaseIIIClinicalTrials GeneralMedicalUse/PhaseIVClinicalTrials
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DevelopmentofAn>-Cancer
Tradi&onally:CancerChemotherapyNa&onalServiceCenter
establishedbytheNCIin1955inordertoscreencompounds
submi>edbyexternalins&tu&onsandcompaniesforan&-cancer
ac&vity.
Exampleistaxol(extractedfromthebarkofthePacificyewtree,Taxusbrevifolia)
Iden&fica&onbasedonEFFICACY,mechanisminterrogatedaOerthefact
analoguesdevelopedandsynthesized
Modern:drugdevelopmentisbasedupontheideaofRa&onal
DrugDesign
TheTARGETisknown,medicinalchemistryallowsthedevelopmentof
compoundswhicharepredictedtobindthetargetofinterest.
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CIDrugScreen
Preliminary:compoundincubatedinvitrowith3differenttumorcelllinesatasingleconcentra5onfor48hours
IfANYac5vity Invitroscreenin60humantumorcelllinesatdifferent
dosesfor48hoursIfpromising
HollowFiberTechnique:12targettumorcelllinesgrowninhollowfibersattwodosesfor4days
And Invivotes5ngusingxenograXs:Humantumorsinjectedsqin
micetreatedwithvariousdosesofcompundfor30days
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Ra)onalDrugDesign
TargetIden5fiedandrecognizedasthesinequanonofthecancerofinterest(egBCR-ABLtyrosinekinasemuta5ongeneproductinCML)
Useofhigh-throughputscreeningofchemicallibraries
toiden5fymoleculesthatbind/inhibittheac5vityoftheTK(iden5fica5onof2-phenylaminopyrimidine)
Compoundtestedandmodifiedbyaddi5onofmethylandbenzamidegroupstoimprovebindingtothe
target,solubility(ima5nib) Pre-clinicaltes5nginanimalmodelsandagainsthumancelllines
ClinicalTrialsdemonstrateefficacy(IRIStrial,NEJM)
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Produc>on,Formula>onand
Drugmetabolism
Chemicalformula)on(issuesofsolubility,
proteinbinding,absorp)on
Dose,frequency,route
Toxicologyinatleasttwoanimalspecies
Large-scaleproduc)onplan
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Inves>ga>onalNewDrugApplica>ons
Requiredforstudiesinvolvinganewagentofunprovenac5vity
TherearethreeINDtypes:
Inves5gatorINDsubmiedbyaphysicianforatrial.Aresearch
INDproposesstudyinganunapproveddrug,oranapproveddrugforanewindica5onoranewpa5entpopula5on.
EmergencyUseINDallowstheFDAtoauthorizeanexperimentaldruginanemergencysitua5on.Usedforptswhodonotmeetthecriteriaofanexis5ngstudyprotocol,orifanapprovedstudyprotocoldoesnotexist.
TreatmentINDsubmiedforexperimentaldrugsshowingpromiseinclinicaltes5ngforseriousorimmediatelylife-threateningcondi5onswhilethefinalclinicalworkisconductedandtheFDAreviewtakesplace.
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IDs(Contd SubmiedeitherbyCommercialorResearchEn))es
IDApplica)onmustcontaininforma)oninthreebroadareas:
AnimalPharmacologyandToxicologyStudies-establishsafetyfor
ini)altes)nginhumans.Includespreviousexperiencew/drugin
humans.
ManufacturingInforma)on-provideinfooncomposi)on,manufacture,stability.Toassureadequateproduc)onandsupplyof
consistentdrug.
ClinicalProtocolsandInves)gatorInforma)on
Detailedprotocolsforproposedclinicalstudiestoassesssafety/risk.
Infoonthequalifica)onsoftheclinicalinves)gators. Commitmenttoobtaininformedconsentfromtheresearchsubjects,reviewbyIRB,
andadherencetoIDregula)ons.
Oncesubmied,sponsormustwait30daysbeforeini)a)nganytrials.
FDAwillreviewtheIDforsafetytoassurethatresearchsubjectswillnot
besubjectedtounreasonablerisk.
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ClinicalProtocols
Maybedesignedby Independentinves)gator
Pharmaceu)calcompany
Mul)centercoopera)vegroups Coopera)veGroupsincludesgeneralhospitals
andcancercentersbasedon
Specificdiseaseareasortreatmentmodali)es(SABP,RTOG
Pa)entpopula)ons(POG
Varietyofcancertypes(CALGB,ECOG,SWOG
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ClinicalProtocols
Designedtoensureuniformityandreproducibilityofproceduresandresearchdesign
Avoidsomissions,s>pulates>mesforspecific
proceduresandensuresstandarddoses,thresholdsandendpoints
Allpersonnelshouldhaveaccesstoawrienprotocolspecifyingtheregimen,inclusioncriteria,
stoppingparametersetc Pharmacistsandoncologynursesserveasaddi>onalchecksinthesystem.
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TopicsCoveredinaProtocol
Coversheet-namesandcontacts
forPI/studynurse
SchemaandSynopsis
Backgroundandra5onale
Objec5ves
Pa5entselec5on
Treatmentplanw/dose
adjustments
Registra5on/randomiza5oninfo,stra5fica5onanddata
management/submission
Requireddataatentryonstudy
andateveryevalua5on
Expectedtoxicityandmanagement
Criteriaforresponse,progressionandrelapse
Removalofpa5entsfromtheapy
Drugformula5on,availability,prepara5on
Adverseevent/reac5on
repor5ng AncillaryTherapy
Sta5s5calconsidera5ons
References
Modelconsentform
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PhaseITrials
ToxicologyINDapplica5on/approvalPhaseI Pa5entsoXenrefractory,pretreated,manydifferentcancertypes
Goalisiden5fica5onofTOICITY Doselimi5ngtoxicity(DLT)isirreversiblegrade3oranygrade4toxicity
Maximumtolerateddose(MTD)ishighestdoseatwhichDLTisseeninlessthan33%ofpa5entsatagivendoselevel
Star5ngdoseis10%oftheLD10inthemostsensi5venon-human
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PhaseITrials(cont
Pa)entsaretreatedincohortsof3-6people
Medica)onDoseescalatedaNer3pa)entsaretreatedwithoutDLT
Medica)ondoseisescalatedusingamodifiedFibonaccisequence:
Ini)alincrease100%,then67%,then50%,40%
then33%eachfurtherincrease LackofresponseinaphaseItrialshouldnot,in
theory,stopfurtherdrugdevelopment
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PhaseIbTrials
ExpansionCohorts
Evaluatepharmacokine)cs/pharmacodynamicsat
recommendedphaseIIdose
Solidtumorbiopsiesaddcomplexitytoimplementa)on
Evaluatefurthertolerabilityatselecteddose
Maylimittocertaintumortypestopreviewefficacy
egher2neuan)body(hercep)ntestedinHer2over-
expressingbreastcancers
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PhaseIITrials
EndpointisRESPOSEwithinspecifictumortype
Candidatesshouldnotbeheavilypretreated
oresponsein14ptssuggestsdrugineffec)ve If1responseobserved,trialexpandedtoupto
30pts
20%responseratesuggestspossibleclinicalu)lity BUT:effec)vedrugscanbefalselyrejected
(duetoincorrectdose/route,heavypriorexposure,poorpa)entPS
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PhaseIIITrials
Endpointisac5vityandtoxicityrela5vetocurrentstandardofcare
Requiresequipoisew.r.t.likelihoodofresponsebetweenthetwoarms
Sizeofthetrialbasedonexpecteddifferenceinendpointsbetweenthenewtreatmentandthestandardofcare.
POWERisthenumberofpa5entsneededtoshowsta5s5callysignificantdifferencesinresponse.
Ifanewtreatmenthasresponseof60%andstandardhasresponseof40%tohavea90%chanceofseeingdifferenceswithp
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PhaseIVStudies
PhaseIIIstudiesdeterminestandardsofcare
Furtherinves)ga)onofefficacyandsafetyof
anapprovedregimenortreatmentor
treatmentinnewanddifferentseng
Postmarke)ngstudiesofsafety
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ReviewofClinicalTrials
PhaseI:Establishestoxicityanddose-schedule
PhaseII:Iden)fiespromisingtherapies
PhaseIII:
Effectoftreatmentrela)vetonaturalhistoryof
disease(fordiseaseswithoutcurrentstandard
Effectoftreatmentrela)vetocurrentstandard
Toxicityoftreatmentrela)vetostandardofcare
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OnceDrughasProvenEfficacy
NewDrugApplica5on(NDA)submiedtotheFDA Providedataonsafetyandefficacyofproposeduse
AnimalStudies,clinicalinfoonPK/PDinforma5on
Appropriatenessofproposedlabeling(packageinsert)
Methodsinmanufacturingandqualitycontrol BiologicLicenseApplica5on(BLA)submiedtotheFDA
Monoclonalan5bodiesforinvivouse
Cytokines,growthfactors,enzymes,immunomoddrugs,
thromboly5cs Proteinsfortherapeu5cuseextractedfromanimalsormicroorganisms
Non-vaccinetherapeu5cimmunotherapies
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FDAApproval
FDAapprovesanewdrugortreatmentbasedonClinicalBenefit.UsusalydatafromPhaseIIorPhaseIItrialsforspecificindica>ons
e.g.taxolapprovedforuseinadvancedovariancancer,metbreastca,andnodeposi5vebreastcancer,butnotforlungcancer(whereitisalsoused)
Determina>onofefficacybasedonresponserates
orsurvivalbutcanalsobebasedonQOLmeasures e.g.gemcitabineapprovalforpancreascancer
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FDAApproval
OncedrugapprovedbytheFDAitcanbeused
outsideitsapprovedindica)on.(e.g.taxol
usedformetlungcancer
Insurerswillusuallyreimbursefordrugsused
outsidelabeledindica)onsaslongasphaseII
dataexitsdemonstra)ngefficacyinthat
diseasearea.
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DifferencesinDevelopmental
Cytotoxics(Taxol)
IDandDevelopment Bruteforcescreeningof1000sof
molecules
Basedonabilitytokillcancercelllineswithlesstoxicitytonormalcells
PhaseI-iden5fyMTD
PhaseII-IVsimilar
MechanismsofAc5on
Inhibi5onofpathwaysforcell
division OXeneffec5veformul5ple
malignancies
TOICITY
Anyrapidlydividingcells
TargetedInhibitors(Ima5nib)
Ra5onalDesign- SpecificTargetsinmind
Highthroughputscreeningforsmall
moleculesthathitthetarget PhaseI-Iden5fytheBiologically
Effec5veDose
PhaseII-IVsimilar
Mechanismknowninadvance,specifictargetsiden5fypossible
usefulness Targetmalignanciesw/thetarget
Inhibitswithoutkillingnormalcells
TOITICY Idiosyncra5c
OXenlesssevere
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