Griffiths Oncology Analysis

7/29/2019 Griffiths Oncology Analysis

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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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Griffiths Oncology Analysis