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Introduction to Medical Oncology and Clinical Trials Elizabeth Griffiths, MD Assistant Professor of Medicine Leukemia Section Roswell Park Cancer Institute [email protected]
IntroductiontoMedicalOncologyandClinicalTrials
ElizabethGriffiths,MDAssistantProfessorofMedicine
LeukemiaSectionRoswellParkCancerInstitute
Outline
• BurdenofDisease
• ModesofTreatmentandSuccesses
• MedicalOncology/HematologyTrainingandImplementation
• DevelopmentalTherapeuticsandTesting
DefinitionandBurdenofDisease
• Oncology:Studyofmalignanttumorsoflethalpotential
• Malignanciescanariseinanytissue,atanyageandspreadbydirectextensionorlymphatic/vascularcirculation
• Canceristhe2ndleadingcauseofdeathintheUSA(1/4USdeaths),3rdworldwide(after♥dz
andinfection)
LifetimeCancerRiskAllSites 1in2 1in3
Prostate 1in6 Breast 1in8Lung/Bronchus 1in13 1in16Colon/Rectum 1in18 1in20Uterus ----- 1in40Bladder 1in27 1in84Melanoma 1in39 1in58NHL 1in45 1in53Kidney 1in57 ------Leukemia 1in67 ------Ovary 1in72OralCavity 1in72 ------Stomach 1in90 ------Cervix ___ 1in145
Source:AmericanCancerSociety,2010
CancerEtiology
• Viral/InfectiousMechanisms(worldwide#1cause,HepB,HPV,EBV,HIV)
• Genetics• Chemicalcarcinogens(tobacco,benzeneetc)• Environmental/IndustrialCarcinogens• Drug-inducedcancers(egsecondaryneoplasia)• Radiationexposure(<1%)
HepatitisBandHepatocellularCarcinoma
ChenCJetal.JAMA.2006;295:65-73.
CancerRate/100Kpopulation
GeneticSusceptibilitiesBRCAMutationCarriers
Canbegenespecificrisk,orpopulationspecificSNPsconferringenhancedrisk
NIH.gov
Smoking
Women
Men
WorldwideSmokingPrevalence(%)
HormoneReplacementTherapyResultspublishedfromthenurseshealthstudy
;Womens’HealthInitiativeJAMA2002.
GeographyandSunExposureUSA
Australia
Site USA Australia
ALL 1in2 1in3
Prostate 1in6 1in5
Lung/Bronchus 1in13 1in12
Colon/Rectum 1in18 1in10
Bladder 1in27 1in39
Melanoma 1in39 1in14
Stomach 1in90 1in55
sunH.pylori
DrugandRadiationInducedCancers
AllanAMandTravisLB.NatureReviewsCancer2005;5:943-955.
StrategiesinCancerManagement
• PrimaryPrevention-– Tobacco,alcohol,dietarychanges,environmentalmanagement,vaccination,antibiotics
• Screeningprograms(earlydetection/2eprevention)– Mammography,PSA/DRE,PapSmears,Colonoscopy
• Treatment-– Surgeryforlocalcontrol– Radiationforloco-regionalmanagement– Oncologywhichincludescytotoxic,hormonal,immunological,targetedandsupportivetherapies
• Palliation
WhatisMedicalOncology?
• MedicalOncologist• Doctorwhospecializesindiagnosingandtreatingcancerusingchemotherapy,hormonetherapyorbiologicaltherapy– OftenthemainhealthcareproviderforsomeonewithCancer
– Providessupportivecareandcoordinatestreatmentbyotherspecialists
FromtheNCIDictionaryhttp://www.cancer.gov/dictionary/?expand=M
MedicalOncologyTraining
• MedicalSchool(4-8yrs)
• InternalMedicineResidency(3yrs)
• Oncology+/-HematologyFellowship(3-5yrs)
PrivatePractice Academics Industry
RoleinCancerPrevention
• Recognitionofsocial,occupational,nutritional,sexualpracticesthatcontributetoneoplasia
• Educationofthegeneralpublicincancerprevention• Smokingisthemostcommoncorrectableriskfactorforcancer(worldwidealsovaccinationforHBV,HPV,preventionofHIV)
• Evaluateandscreenappropriatelypopulationsatincreasedgeneticcancerrisk(BRCA,HNPCC,APC,p53,Rbfamilies)
CancerDiagnosis• Requireshistologicproofonatleastoneoccasion
• Newsymptomsinapatientwithapriorhistoryofcancerneedextensive/exhaustiveevaluation
• Nosymptomsshouldbeattributedtocancerwithoutbiopsyevidence,BUTcancershouldalwaysbeonthedifferential
• Cancerpatientscanalsohaveothersymptomaticdiseases
“Chemotherapy”
• Chemicals(usuallygene-toxins,butnowmoretargetedtherapyaswell)usedtotreatorcontrolcancer
• Oncologistresponsibleforappropriatedruganddosecombination
• Drug(s)useddependoncancertype,stage,patientageandcomorbidities
• Managementofsideeffects
PrinciplesofTreatment
• Whereisthetumor?Whateffectdoesithaveonnormalorganstructure/function?
• Howtoxicisthetreatmenttosurrounding/systemicnormaltissues
• IstreatmentpotentiallyCURATIVE?OrisitPALLIATIVE(decreasedsx,improvedQOL)
LawsofTherapeutics
I-ifitisworking,keepitup– Primumnonnocere-subjecttoconstantreassessmentinoncology.Curativeandsub-curativestrategiesarealmostalwaystoxic,howmuchriskisworthit?
II-Ifitisisn’thelping,stopdoingit.III-ifyoudon’tknowwhattodo,donothing.– Askyourcolleagues,gototumorboard.
IV-Thetreatmentshouldn’tbeworsethatthedisease
PrinciplesofChemotherapy
TherapeuticApproaches
• Local/Regional– Surgery– Radiation,PDT– Chemotherapy(egintravesical,intrathecal,topical,hepaticarterialchemoembolization)
• Systemic– Chemotherapy(cytotoxic,hormonal,immunologic,tyrosinekinaseinhibitors)
– SupportiveCare(anti-emetics,growthfactors,narcotics
CombinedTherapies
Neo-Adjuvant
• Chemotherapyand/orradiationgivenbeforesurgery– Ideaistoshrinkthetumortoallowsmallerresectionsororganpreservation(egforheadandneck,breast,pancreascancersorsarcomas)
– Responsetotreatmentgivesaninvivotestofchemosensitivity/resistance(sarcomas)andcanprovideprognosticinformationinsomecases
–Mayenhancetheefficacyofradiationsoastoavoidtheneedforsurgery.
AdjuvantTherapy
• Post-SurgicalChemotherapyand/orRadiation– GivenAFTERthesurgerytoimprovelocalcontrol,decreaseriskofmetastaticdiseaseandprolongsurvival
– Canoffercureforsometumorswheresurgeryalonehasalowcurerate(ieWilms’Tumor,Osteosarcomas)
– ProlongsdiseasefreeintervalforstageIIorIIIbreastcancer,StageIIIovariancancersandStage(II)/IIIColonCancers,PancreaticCancersallstages,LungCancersIb,II,IIIpostsurgery
TargetedTherapies
• “medicationswhichblockthegrowthofcancercellsbyinterferingwithspecificmoleculartargetsneededforcarcinogeneis/growth/metasteses,ratherthanbygenotoxicstress”
• Moreeffective/lessharmfultonormalcells• NewParadigms-trialdesign,stabilityvsremission– MonoclonalAntibodies– TyrosineKinaseInhibitors– Vaccines
UpfrontChemotherapy
• Fordiseaseswhicharenottreatablewithlocalmeasures
• Formostsolidtumorsthegoalisusuallyprolongationofsurvivalratherthancure– systemicallyadministereddrugstoslowthegrowthoftumorcells,decreasetheburdenofmetastaticdisease
• BUT:SomeCancersarecurablewithChemotherapyalone
CancersTreatable/CurablewithChemotherapyAlone
• AcuteLymphoblasticLeukemia/Lymphomainchildren
• Seminomas• HodgkinLymphoma• ClassicalBurkittLeukemia/Lymphoma• PromyelocyticLeukemia• DiffuselargeBcellLymphoma• HairyCellLeukemia• ChronicMyelogenousLeukemia
CurablewithCombinedModality(Chemo+XRTorSurgery/Chemo/XRT)
• Non-MetastaticCarcinomas– SomeearlyStagelungcancers– Headandneckcancers– EarlyStageGastricoresophagealcancers– BreastCancer(maybe)– ProstateCancer(maybe)– OvarianCancers(maybe)– Sarcomas(some,aslongastheyaresmall)
WhatabouttheRest??
• Bottomline:– Metastaticcancerisrarelycurable– Evencancerstreatedatearlystagesometimeshavemicrometastaseswhich
showuplater– Cancersthatrelapseareoftendifficulttotreatduetoacquisitionof
resistancetochemotherapy
• SO:– Wetryhighdosetherapy(i.e.auto-transplantforbreastcancer)– Givegrowthfactorstotryandallowhigherdosesofchemo,more
frequently(DoseDensity)– Combinedifferentdrugsgivensequentiallytodecreasetoxicityandavoid
resistance(PROmaceCYTABOM,CHOP,hyperCVAD)– Trynewdrugs/drugcombinations(CLINICALTRIALS)
CancerDrugDevelopment
Steps
• NovelCompoundIdentification(pre-clinical)• ProductionandFormulation• Toxicologyevaluationinvivo• PhaseIClinicalTrials• PhaseIIClinicalTrials• PhaseIIIClinicalTrials• GeneralMedicalUse/PhaseIVClinicalTrials
DevelopmentofAnti-CancerCompounds
– Traditionally:CancerChemotherapyNationalServiceCenterestablishedbytheNCIin1955inordertoscreencompoundssubmittedbyexternalinstitutionsandcompaniesforanti-canceractivity.• Exampleistaxol(extractedfromthebarkofthePacificyewtree,Taxus
brevifolia)• IdentificationbasedonEFFICACY,mechanisminterrogatedafterthefact• analoguesdevelopedandsynthesized
– Modern:drugdevelopmentisbasedupontheideaof“RationalDrugDesign”• TheTARGETisknown,medicinalchemistryallowsthedevelopmentof
compoundswhicharepredictedtobindthetargetofinterest.
NCIDrugScreen
• Preliminary:compoundincubatedinvitrowith3differenttumorcelllinesatasingleconcentrationfor48hours
IfANYactivity →• Invitroscreenin60humantumorcelllinesat5different
dosesfor48hoursIfpromising→• HollowFiberTechnique:12targettumorcelllinesgrownin
hollowfibersattwodosesfor4daysAnd→• Invivotestingusingxenografts:Humantumorsinjectedsqin
micetreatedwithvariousdosesofcompoundfor30days
RationalDrugDesign
• TargetIdentifiedandrecognizedasthesinequanonofthecancerofinterest(egBCR-ABLtyrosinekinasemutationgeneproductinCML)
• Useofhigh-throughputscreeningofchemicallibrariestoidentifymoleculesthatbind/inhibittheactivityoftheTK(identificationof2-phenylaminopyrimidine)
• Compoundtestedandmodifiedbyadditionofmethylandbenzamidegroupstoimprovebindingtothetarget,solubility(imatinib)
• Pre-clinicaltestinginanimalmodelsandagainsthumancelllines
• ClinicalTrialsdemonstrateefficacy(IRIStrial,NEJM)
Production,FormulationandToxicology
• Drugmetabolism• Chemicalformulation(issuesofsolubility,proteinbinding,absorption)
• Dose,frequency,route• Toxicologyinatleasttwoanimalspecies• Large-scaleproductionplan
InvestigationalNewDrugApplications(IND)
• Requiredforstudiesinvolvinganewagentofunprovenactivity• TherearethreeINDtypes:
– InvestigatorINDsubmittedbyaphysicianforatrial.AresearchINDproposesstudyinganunapproveddrug,oranapproveddrugforanewindicationoranewpatientpopulation.
– EmergencyUseINDallowstheFDAtoauthorizeanexperimentaldruginanemergencysituation.Usedforptswhodonotmeetthecriteriaofanexistingstudyprotocol,orifanapprovedstudyprotocoldoesnotexist.
– TreatmentINDsubmittedforexperimentaldrugsshowingpromiseinclinicaltestingforseriousorimmediatelylife-threateningconditionswhilethefinalclinicalworkisconductedandtheFDAreviewtakesplace.
INDs(Cont’d)• SubmittedeitherbyCommercialorResearchEntities• INDApplicationmustcontaininformationinthreebroadareas:
– AnimalPharmacologyandToxicologyStudies-establishsafetyforinitialtestinginhumans.Includespreviousexperiencew/druginhumans.
– ManufacturingInformation-provideinfooncomposition,manufacture,stability.Toassureadequateproductionandsupplyofconsistentdrug.
– ClinicalProtocolsandInvestigatorInformation• Detailedprotocolsforproposedclinicalstudiestoassesssafety/risk.• Infoonthequalificationsoftheclinicalinvestigators.• Commitmenttoobtaininformedconsentfromtheresearchsubjects,reviewbyIRB,
andadherencetoINDregulations.• Oncesubmitted,sponsormustwait30daysbeforeinitiatinganytrials.
FDAwillreviewtheINDforsafetytoassurethatresearchsubjectswillnotbesubjectedtounreasonablerisk.
ClinicalProtocols• Maybedesignedby– Independentinvestigator– Pharmaceuticalcompany–Multicentercooperativegroups
• CooperativeGroupsincludesgeneralhospitalsandcancercentersbasedon– Specificdiseaseareasortreatmentmodalities(NSABP,RTOG)
– Patientpopulations(POG)– Varietyofcancertypes(CALGB,ECOG,SWOG)
ClinicalProtocols
• Designedtoensureuniformityandreproducibilityofproceduresandresearchdesign
• Avoidsomissions,stipulatestimesforspecificproceduresandensuresstandarddoses,thresholdsandendpoints
• Allpersonnelshouldhaveaccesstoawrittenprotocolspecifyingtheregimen,inclusioncriteria,stoppingparametersetc
• Pharmacistsandoncologynursesserveasadditionalchecksinthesystem.
TopicsCoveredinaProtocol• Coversheet-namesandcontacts
forPI/studynurse• SchemaandSynopsis• Backgroundandrationale• Objectives• Patientselection• Treatmentplanw/dose
adjustments• Registration/randomizationinfo,
stratificationanddatamanagement/submission
• Requireddataatentryonstudyandateveryevaluation
• Expectedtoxicityandmanagement
• Criteriaforresponse,progressionandrelapse
• Removalofpatientsfromtherapy• Drugformulation,availability,
preparation• Adverseevent/reactionreporting• AncillaryTherapy• Statisticalconsiderations• References• Modelconsentform
PhaseITrials
• Toxicology→INDapplication/approval →PhaseI
• Patients →oftenrefractory,pretreated,manydifferentcancertypes
• GoalisidentificationofTOXICITY– Doselimitingtoxicity(DLT)isirreversiblegrade3oranygrade4toxicity
– Maximumtolerateddose(MTD)ishighestdoseatwhichDLTisseeninlessthan33%ofpatientsatagivendoselevel
– Startingdoseis10%oftheLD10inthemostsensitivenon-humanspecies(sometimesproblematicintargetedrxs)
PhaseITrials(cont)
• Patientsaretreatedin“cohorts”of3-6people• MedicationDoseescalatedafter3patientsaretreatedwithoutDLT
• MedicationdoseisescalatedusingamodifiedFibonaccisequence:– Initialincrease100%,then67%,then50%,40%then33%eachfurtherincrease
• LackofresponseinaphaseItrialshouldnot,intheory,stopfurtherdrugdevelopment
PhaseIbTrials
• ExpansionCohorts– Evaluatepharmacokinetics/pharmacodynamicsatrecommendedphaseIIdose• Solidtumorbiopsiesaddcomplexitytoimplementation• Evaluatefurthertolerabilityatselecteddose• Maylimittocertaintumortypestopreviewefficacy
– egher2neuantibody(herceptin)testedinHer2over-expressingbreastcancers
PhaseIITrials
• EndpointisRESPONSEwithinspecifictumortype
• Candidatesshouldnotbeheavilypretreated• Noresponsein14ptssuggestsdrugineffective– If≥1responseobserved,trialexpandedtoupto30pts
– 20%responseratesuggestspossibleclinicalutility• BUT:effectivedrugscanbefalselyrejected(duetoincorrectdose/route,heavypriorexposure,poorpatientPS)
PhaseIIITrials
• EndpointisACTIVITYANDTOXICITYrelativetocurrentstandardofcare– Requiresequipoisew.r.t.likelihoodofresponsebetweenthetwoarms
• Sizeofthetrialbasedonexpecteddifferenceinendpointsbetweenthenewtreatmentandthestandardofcare.
• “POWER”isthenumberofpatientsneededtoshowstatisticallysignificantdifferencesinresponse.– Ifanewtreatmenthasresponseof60%andstandardhasresponseof40%tohavea90%chanceofseeingdifferenceswithp<0.05youneed139patientsineacharm
PhaseIVStudies
• PhaseIIIstudiesdetermineSTANDARDSOFCARE
• Furtherinvestigationofefficacyandsafetyofanapprovedregimenortreatmentortreatmentinnewanddifferentsetting
• Postmarketingstudiesofsafety
ReviewofClinicalTrials
• PhaseI:Establishestoxicityanddose-schedule• PhaseII:Identifiespromisingtherapies• PhaseIII:– Effectoftreatmentrelativetonaturalhistoryofdisease(fordiseaseswithoutcurrentstandard)
– Effectoftreatmentrelativetocurrentstandard– Toxicityoftreatmentrelativetostandardofcare
OnceDrughasProvenEfficacy
• NewDrugApplication(NDA)submittedtotheFDA– Providedataonsafetyandefficacyofproposeduse
• AnimalStudies,clinicalinfoonPK/PDinformation– Appropriatenessofproposedlabeling(packageinsert)– Methodsinmanufacturingandqualitycontrol
• BiologicLicenseApplication(BLA)submittedtotheFDA– Monoclonalantibodiesforinvivouse– Cytokines,growthfactors,enzymes,immunomoddrugs,thrombolytics
– Proteinsfortherapeuticuseextractedfromanimalsormicroorganisms
– Non-vaccinetherapeuticimmunotherapies
FDAApproval
• FDAapprovesanewdrugortreatmentbasedon“ClinicalBenefit.”UsusalydatafromPhaseIIorPhaseIItrialsforspecificindications– e.g.taxolapprovedforuseinadvancedovariancancer,metbreastca,andnodepositivebreastcancer,butnotforlungcancer(whereitisalsoused)
• DeterminationofefficacybasedonresponseratesorsurvivalbutcanalsobebasedonQOLmeasures– e.g.gemcitabineapprovalforpancreascancer
FDAApproval
• OncedrugapprovedbytheFDAitcanbeusedoutsideit’sapprovedindication.(e.g.taxolusedformetlungcancer)
• InsurerswillusuallyreimbursefordrugsusedoutsidelabeledindicationsaslongasphaseIIdataexitsdemonstratingefficacyinthatdiseasearea.
DifferencesinDevelopmentalParadigms
• Cytotoxics(Taxol) • IDandDevelopment
– Bruteforcescreeningof1000sofmolecules
– Basedonabilitytokillcancercelllineswithlesstoxicitytonormalcells
– PhaseI-identifyMTD– PhaseII-IVsimilar
• MechanismsofAction– Inhibitionofpathwaysforcelldivision– Ofteneffectiveformultiple
malignancies• TOXICITY
– Anyrapidlydividingcells
• TargetedInhibitors(Imatinib)• RationalDesign-
– SpecificTargetsinmind• Highthroughputscreeningforsmall
moleculesthathitthetarget– PhaseI-IdentifytheBiologically
EffectiveDose– PhaseII-IVsimilar
• Mechanismknowninadvance,specifictargetsidentifypossibleusefulness– Targetmalignanciesw/thetarget– Inhibitswithoutkillingnormalcells
• TOXITICY– Idiosyncratic– Oftenlesssevere
2010EstimatedUSCancerCases
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%)NHL 35,380(4%) NHL 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%)
2010EstimatedUSCancerDeaths
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%) NHL 9,500(4%)Esophagus 11,650(4%) Leukemia 9,180(3%)NHL 10,710(4%) Uterine 7,950(3%)Bladder 10,410(3%) Liver/bileduct 6,190(2%)Kidney 8,210(3%) Brain/Nervous 5,720(2%)
Other 69,220(23%) 63,160(23%)
Mortality
153300/222520(69%)71890/424820(17%)51370/142570(36%)18770/21770(88%)
