Phase-II-Trials-Methods-in-Clinical-Cancer-ResearchII期试验方法在临床癌症的研究课件

PhaseIIClinicalTrialsMiguelVillalona-Calero,MD.,FACPTheOhioStateUniversity2019AACR/ASCOWorkshopPhaseIIClinicalTrialsMiguel1QuestionWhatpercentageoftheconceptssubmittedbyyouarePhase2trialsorthePhase2trialisitsmaincomponent?20%40%50%60%QuestionWhatpercentageofthe2InteractiveAnswerInteractiveAnswer3OverviewObjectives&ConceptDevelopmentDesignEndpointsOutcomesMeasuresSampleSizeCalculationExamplesOverviewObjectives&ConceptD4ObjectivesTodefineantitumoractivity.Todemonstratesafety.Togainnewinsightsintothepharmacokinetics,pharmacodynamicsandmetabolismoftherapeuticagents.Toevaluatebiologiccorrelateswhichmaypredictresponseorresistancetotreatmentand/ortoxicity.ObjectivesTodefineantitumor5ConceptDevelopmentTheWhatTheWhoTheHowSimpleandfunModerateandexcitingHardandfrustratingConceptDevelopmentTheWhatSi6TheWhatWhatisyourhypothesis?Isitsound?DoabackgroundcheckWhathasbeenwritten?Whatisbeingtestedatpresent?ReviewyourpreclinicalandphaseIdatawellDrawanillustrationSellittoyourspouseSellittoacolleageTheWhatWhatisyourhypothesi7TheWhoWhodoyouwantyourconcepttestedin?DefineyourpopulationDefinethestandardofcareDefinehistoricaloutcomeswithstandardofcareDecideondoseandschedulePriortreatmentallowedDiscusswithyourmentorandwithanexperiencedfacultymemberTheWhoWhodoyouwantyourco8TheHowHowwillyoudoit?CometoVail?SelectyourtrialdesignSelectyourendpointsandoutcomemeasuresSelectyoursamplesizeTheHowHowwillyoudoit?9II.StudyDesignsSingleArmTwoormorearmsII.StudyDesignsSingleArm10II.StudyDesignsFrequentistGehan2-StageSimon2-StageOptimalSimon2-StageMinimaxFleming1-stageGehan-Simon3-StageRandomizedPhase2ConstantArc-SineRandomizedDiscontinuationBayesianThall-Simon-Estey1-StageBayesian2-StageBayesianTanMachinHeitjanAdaptiveMultipleOutcomesII.StudyDesignsFrequentistBa11Two-stageDesignMainobjectiveistominimizethenumberofpatientstreatedwithineffectiveregimensAverycommonlyused2stagedesignistheSimon,whichminimizessamplesizebasedonapre-specifiedresponserateandananderrorrates.Optimal:minimizesthe#ofptstreatediftheregimenisineffectiveMinimax:minimizesthewholesamplesize

RecistResponse[CR+PR+SD]isgenerallyutilized.Simonetal,ContClinTrials,1989Two-stageDesignMainobjectiv12Simon,Mini-maxTreat~12-18patientsat1ststageDeterminethe“responserate”Lessthanthatprojectedtoindicateactivity(p0):STOP!Sufficientlygreattoindicateactivity:CONTINUEAttheendof2ndstage,declaredrug/interventionworthyoffurtherevaluationif>xnumberof“responses”areobserved(p1)Simon,Mini-maxTreat~12-18pa13One-stageDesignWhentime-dependentendpointsareconsidered e.g.,theproportionofpatientsfreeofprogressionatoneyearfollowinginitiationoftreatment.

Giventhetimeperiodfrominitiationoftreatmenttotheendpoint,two-stagedesignsareoftenimpractical.Earlystoppingrulesareusuallyincorporatedforobviouslackofefficacyorunacceptabletoxicity.Biometrics,1982One-stageDesignWhentime-depe14One-stageDesignFlemingisthemostcommonlyutilizedone-stagedesign.Youneedtohaveagoodgriponhistoricalcontroldata.MickDesign:Comparetimetotreatmentfailureorprogressiononthenewregimen[TTP2]withtheindividualpatient’sfailuretimeorTTP1observedwiththeirpriorregimen.

IftheTTP2/TTP1ratioisgreaterthan1.33,theregimenisconsideredeffectiveandworthyoffurtherstudy.JClinOncol,2019ContClinTrials,2000One-stageDesignFlemingisthe15RandomizedPhaseIITrialsPatientsarerandomizedtoreceiveoneoftwo(ormore)regimensdifferingbydoselevel,schedule,orspecificagent.Itisnotpoweredtomakeinferentialcomparisonsbetweenthetreatmentarms.Pickthewinnerapproach.Ifbotharmsincorporatetwo-stagedesigns,youwouldhavefourspecificdecisionpointsfordeterminingefficacy.Simonetal,CancerTreatRep,1985Liuetal,ControlClinTrials,2019RandomizedPhaseIITrialsPati16RandomizedDiscontinuationItincorporatestime-dependentendpointswithdiseaseresponse.Stablediseasepatientsarerandomizedtocontinuationwiththeagentorplacebo(thediscontinuation)Patientssubsequentlyshowingprogressiononplaceboarethenretreatedwiththeagenttodetermineifstabilitycanberegained.Thisdesignismostappropriateindiseaseswheretumorgrowthratesareslow.Kopec,JClinEpidemiol,1993Rosner(JClinOncol,2019RandomizedDiscontinuationIti17ExamplesExamples18PhaseIITrialofGefitinibinPatients

WithAdvancedNSCLC:EfficacyMedianoverallsurvivalinthe250mg/dand500mg/dgefitinibgroups

were7monthsand6months,respectively(P=0.40)Projected1-yearsurvivalrateswere27%and24%,respectively(P=0.54)P=0.51P=0.26Krisetal.JAMA.2019;290:2149.PhaseIITrialofGefitinibin19Single-AgentNexavarin3rdline+NSCLC:Double-blindPhaseIIECOG2501,JoanSchiller,MD.AStableDiseasePDDiscontinueProtocolTreatmentPRContinueNexavarprotocoltreatmentArm1NexavarpobidArm2PlacebopobidSCANRANDOMIZENexavar

pobidX2cycles(8weeks)PDPopulationStageIIIBandIV2ormorepriorchemotherapyregimens≥18yearsofageECOGPS0–1AsymptomaticbrainmetastasesallowedSampleSizeN=330accrued,98randomizedEndpoints1stendpoint:SDorresponseafter2coursesoftreatmentpostrandomization2ndendpoint:PFS,RR,SurvivalBSecond:Randomizedpatientsfirstevaluatedforprogressionafteranother8weeksFirst:PatientsevaluatedforSDat8weeksASCOAbstr8014.

Single-AgentNexavarin3rdli20EndpointOutcomeMeasuresRECIST/WHOResponseRateCR+PRCR+PR+SDTimetoFailure/SurvivalProgression-FreeRateDisease-FreeRateEndpointOutcomeMeasuresRECIS21EndpointOutcomeMeasuresBiologicalEndpointsSafety&AdverseEventsMultipleEndpointsQOLEndpointOutcomeMeasuresBiolo22CorrelativeStudiesImportant,hypothesis-generating,exploratorystudiesHowever,don’tdothembecauseeveryoneelseis…..BUTduringcourseofstudy:ValidationoftargetsandassaysmayoccurNewmarkersandpathwaysmaybeidentifiedConsidercollectingspecimenstoevaluateonlyifactivitysignalsareseeninstageI(for2-stagedesigns)CorrelativeStudiesImportant,23SampleSizeCalculationPriordeterminationofthesamplesizethatisneededtoshowanimportantdifferenceisessential.

Twoerrorscanbemadeinatestofahypothesis:rejectingthenullhypothesiswhenitistrue(TypeIError,)(false-positive)notrejectingthenullhypothesiswhenitisfalse(TypeII,)(false-negative).

AnotherimportantconsiderationisPower;theprobabilityofrejectingthenullhypothesiswhenitisfalse,orofconcludingthealternativehypothesiswhenitistrue.FromBasic&ClinicalBiostatisticsDawson-SaundersandTrappeds.SampleSizeCalculationPriord24SampleSizeCalculationBeforegoingtoyourstatisticianWhatisthedesiredlevelofsignificanceofthenullhypothesis(0)?Whatchanceshouldtherebeofdetectinganactualdifference(whatpower)associatedwiththealternativehypothesis(1)isdesired?Howlargeshouldthedifferencebetweentheproportions(1-

0)beinorderforittohaveclinicalimportance?Whatisagoodestimateofthestandarddeviationinthepopulation?ThevalueofthenullhypothesisdeterminesinmostcasesthestandarddeviationFromBasic&ClinicalBiostatisticsDawson-SaundersandTrappeds.SampleSizeCalculationBefore25N=Z0(1-0)-Z1(1-1)1-02SYSTAT,MINITAB,STATISTIXPASSN=Z0(1-0)-Z1(1-126Giventhiscomplexityofdesignandoutcomealternatives,theselectionofatrialdesignrequiresclosecollaborationbetweenthestudyinvestigatorandclinicalbiostatisticianstoclearlydefinestudyobjectives,toselectappropriateendpoints,toselectatrialdesign,andtocomputetherequirednumberofpatientstobeenrolled.

Weshouldindividualizethetrialdesignandoutcomemeasurestotheparticularagent(orcombination)anddiseaseorsubsetofdiseasetobeevaluated.Giventhiscomplexityofdesig27MyExamplesPhase2StudyofCapecitabineandDocetaxelinPreviouslyUntreatedadvancedNon-SmallCellLungCancerPatients(OSU-0356).NCIR21CA108157

Phase2trialofSequentiallyAdministeredCPT-11andMitomycinCinPatientswithAdvancedEsophagealandStomachCancer(OSU-0151).NCIR21CA92956Phase1/2StudyofEtanerceptandGemcitabineinPatientswithAdvancedStageandChemotherapy-NaïvePancreaticAdenocarcinoma(OSU-0041).NCIR21CA101360

MyExamplesPhase2StudyofCa28Phase2StudyofCapecitabine/DocetaxelinPreviouslyUntreatedAdvancedNSCLCPatientsCapecitabinelastconversionstepismediatedbythymidinephosphorylase(TF),whichispreferentiallyexpressedintumorsPreclinicalstudiessuggestthatpaclitaxel/docetaxelincreaseexpressionofTFAprevioustrialinpretreatedNSCLCpatients(n=31)showeda26%RR,25%26-wksPFS,MS9.1m,1-yearsurvival37%Phase2StudyofCapecitabine/29Howwouldyoudesignit?Simon2-stageMinimaxFleming1-stageRandomizedPhase2MickDesignRandomizedDiscontinuationHowwouldyoudesignit?Simon30InteractiveAnswerInteractiveAnswer31OurDesignEndpointRECISTobjectiveresponse(PR/CR)SimonTwo-stageminimax<30%nointerest,50%interestIf8ormorepatientsshowresponsesinthefirst28,11additionalpatientsaretreatedforatotalof39.If15showresponses,theregimenwillnotberecommendedforfurtherstudy.If16patientsshowresponsesinthe39,theregimenwillbestudiedfurther.

OurDesignEndpointRECISTobje32PotentialAlternatives?Fleming1-stage(yes,iftimedependentendpointswerechosen)RandomizedPhase2(yes,ifmulti-institutional)MickDesign(no,firstlinetreatment)RandomizedDiscontinuation(noforaggressivemalignancy,moreappropriatetotestdurabilityofefficacyorsignificanceofstability)PotentialAlternatives?Fleming33Phase2trialofSequentiallyAdministeredCPT-11andMitomycinCinPatientswithAdvancedEsophagealandStomachCancerIrinotecan(CPT-11)isatopoisomerase1(Topo1)interactiveagent.DecreasedlevelsofTopo1isamechanismofresistance

PreclinicalstudiesshowedthatmitomycinCupregulateactivityofTopo1,thusmodulationofTopo1activitybyMMCmayresultinincreasedresponsetoCPT-11MitomycinChasmanysideeffects,sodoctorshateit.AphaseItrialestablished6mg/m2onday1,followedbyCPT-11125mg/m2days2and9,every28daysassafe,andshowed5responsesinrefractoryesophagealcancerpatientsPhase2trialofSequentially34Howwouldyoudesignit?Simon2-stageMinimaxFleming1-stageRandomizedPhase22-stageBayesianRandomizedDiscontinuationHowwouldyoudesignit?Simon35InteractiveAnswerInteractiveAnswer36TwoArms,randomizedparallelSimonMini-MaxMMC6mg/m2onday1andirinotecan125mg/m2ondays2and9,withcyclesrepeatedevery4weeks.

MMC,3mg/m2ondays1andday8,priortoirinotecan125mg/m2ondays2and9,every4weeks.AcapinthedoseofMMCof36mg/m2wasenforced.

OurDesignTwoArms,randomizedparallel37PotentialAlternatives?Simon2-stageMinimax(yes,buthistoricalcontrolsshaky)Fleming1-stage(nosinceotherinterventionsmayfollow,timedependentend-pointsnotreliable).RandomizedPhase22-stageBayesian(yes,ifyourstatssupportisactiveonthis)RandomizedDiscontinuation(no,asperB)PotentialAlternatives?Simon238Phase1/2StudyofEtanerceptandGemcitabineinPatientswithAdvancedStageandChemotherapy-NaïvePancreaticAdenocarcinomaPancreaticcancerpatientsareoftencacquectic,haveverypoorqualityoflifeandadismalsurvivalGemcitabineisstandardofcareinmetastaticpancreaticcancermainlyduetoqualityoflifeimprovementsTumornecrosisfactorhavebeenshowntoplayaroleincaquexiaandtostimulatecancergrowththroughNF-kBEtanerceptisadecoyreceptorofTNFandyouwonderifaddingittogemcitabinecanresultinimprovementsinqualityoflifeanddiseaseprogression.Phase1/2StudyofEtanercept39Howwouldyoudesignit?Simon2-stageMinimaxFleming1-stageRandomizedPhase22-stageBayesianRandomizedDiscontinuationHowwouldyoudesignit?Simon40InteractiveAnswerInteractiveAnswer41OurDesignSingleStageFlemingProgression-FreeRateat6Months(>7/25).MedianSurvivalandSurvivalat6and12months.AssessmentofClinicalBenefitResponsePainIntensity(MPAC)AnalgesicUseWeightChangeECOGPSQualityofLifeCorrelationofcytokinesandClinicalBenefitResponse.OurDesignSingleStageFleming42PotentialAlternatives?Simon2-stageMinimax(no,timedependentendpointsandQOLbeingconsidered)Fleming1-stage

RandomizedPhase2(yes,ifbotharmsflemingandmulti-institutional)2-stageBayesian(yes,ifyourstatssupportisactiveonthis)RandomizedDiscontinuation(tooaggressive)PotentialAlternatives?Simon243ConclusionsPhaseIItrialsareexploratorystudiesandrarelyaredefinitiveEfficienttoexcludeinactivetherapiesResultsmustbeinterpretedcautiously,inthecontextoftheavailabilityofothertherapiesEstimateclinicalactivityandprovidefurthersafetyinformation–importantinthe“go/nogo”decisionRequireconfirmationinphaseIIItrialsConclusionsPhaseIItrialsare44PhaseIIClinicalTrialsMiguelVillalona-Calero,MD.,FACPTheOhioStateUniversity2019AACR/ASCOWorkshopPhaseIIClinicalTrialsMiguel45QuestionWhatpercentageoftheconceptssubmittedbyyouarePhase2trialsorthePhase2trialisitsmaincomponent?20%40%50%60%QuestionWhatpercentageofthe46InteractiveAnswerInteractiveAnswer47OverviewObjectives&ConceptDevelopmentDesignEndpointsOutcomesMeasuresSampleSizeCalculationExamplesOverviewObjectives&ConceptD48ObjectivesTodefineantitumoractivity.Todemonstratesafety.Togainnewinsightsintothepharmacokinetics,pharmacodynamicsandmetabolismoftherapeuticagents.Toevaluatebiologiccorrelateswhichmaypredictresponseorresistancetotreatmentand/ortoxicity.ObjectivesTodefineantitumor49ConceptDevelopmentTheWhatTheWhoTheHowSimpleandfunModerateandexcitingHardandfrustratingConceptDevelopmentTheWhatSi50TheWhatWhatisyourhypothesis?Isitsound?DoabackgroundcheckWhathasbeenwritten?Whatisbeingtestedatpresent?ReviewyourpreclinicalandphaseIdatawellDrawanillustrationSellittoyourspouseSellittoacolleageTheWhatWhatisyourhypothesi51TheWhoWhodoyouwantyourconcepttestedin?DefineyourpopulationDefinethestandardofcareDefinehistoricaloutcomeswithstandardofcareDecideondoseandschedulePriortreatmentallowedDiscusswithyourmentorandwithanexperiencedfacultymemberTheWhoWhodoyouwantyourco52TheHowHowwillyoudoit?CometoVail?SelectyourtrialdesignSelectyourendpointsandoutcomemeasuresSelectyoursamplesizeTheHowHowwillyoudoit?53II.StudyDesignsSingleArmTwoormorearmsII.StudyDesignsSingleArm54II.StudyDesignsFrequentistGehan2-StageSimon2-StageOptimalSimon2-StageMinimaxFleming1-stageGehan-Simon3-StageRandomizedPhase2ConstantArc-SineRandomizedDiscontinuationBayesianThall-Simon-Estey1-StageBayesian2-StageBayesianTanMachinHeitjanAdaptiveMultipleOutcomesII.StudyDesignsFrequentistBa55Two-stageDesignMainobjectiveistominimizethenumberofpatientstreatedwithineffectiveregimensAverycommonlyused2stagedesignistheSimon,whichminimizessamplesizebasedonapre-specifiedresponserateandananderrorrates.Optimal:minimizesthe#ofptstreatediftheregimenisineffectiveMinimax:minimizesthewholesamplesize

RecistResponse[CR+PR+SD]isgenerallyutilized.Simonetal,ContClinTrials,1989Two-stageDesignMainobjectiv56Simon,Mini-maxTreat~12-18patientsat1ststageDeterminethe“responserate”Lessthanthatprojectedtoindicateactivity(p0):STOP!Sufficientlygreattoindicateactivity:CONTINUEAttheendof2ndstage,declaredrug/interventionworthyoffurtherevaluationif>xnumberof“responses”areobserved(p1)Simon,Mini-maxTreat~12-18pa57One-stageDesignWhentime-dependentendpointsareconsidered e.g.,theproportionofpatientsfreeofprogressionatoneyearfollowinginitiationoftreatment.

Giventhetimeperiodfrominitiationoftreatmenttotheendpoint,two-stagedesignsareoftenimpractical.Earlystoppingrulesareusuallyincorporatedforobviouslackofefficacyorunacceptabletoxicity.Biometrics,1982One-stageDesignWhentime-depe58One-stageDesignFlemingisthemostcommonlyutilizedone-stagedesign.Youneedtohaveagoodgriponhistoricalcontroldata.MickDesign:Comparetimetotreatmentfailureorprogressiononthenewregimen[TTP2]withtheindividualpatient’sfailuretimeorTTP1observedwiththeirpriorregimen.

IftheTTP2/TTP1ratioisgreaterthan1.33,theregimenisconsideredeffectiveandworthyoffurtherstudy.JClinOncol,2019ContClinTrials,2000One-stageDesignFlemingisthe59RandomizedPhaseIITrialsPatientsarerandomizedtoreceiveoneoftwo(ormore)regimensdifferingbydoselevel,schedule,orspecificagent.Itisnotpoweredtomakeinferentialcomparisonsbetweenthetreatmentarms.Pickthewinnerapproach.Ifbotharmsincorporatetwo-stagedesigns,youwouldhavefourspecificdecisionpointsfordeterminingefficacy.Simonetal,CancerTreatRep,1985Liuetal,ControlClinTrials,2019RandomizedPhaseIITrialsPati60RandomizedDiscontinuationItincorporatestime-dependentendpointswithdiseaseresponse.Stablediseasepatientsarerandomizedtocontinuationwiththeagentorplacebo(thediscontinuation)Patientssubsequentlyshowingprogressiononplaceboarethenretreatedwiththeagenttodetermineifstabilitycanberegained.Thisdesignismostappropriateindiseaseswheretumorgrowthratesareslow.Kopec,JClinEpidemiol,1993Rosner(JClinOncol,2019RandomizedDiscontinuationIti61ExamplesExamples62PhaseIITrialofGefitinibinPatients

WithAdvancedNSCLC:EfficacyMedianoverallsurvivalinthe250mg/dand500mg/dgefitinibgroups

were7monthsand6months,respectively(P=0.40)Projected1-yearsurvivalrateswere27%and24%,respectively(P=0.54)P=0.51P=0.26Krisetal.JAMA.2019;290:2149.PhaseIITrialofGefitinibin63Single-AgentNexavarin3rdline+NSCLC:Double-blindPhaseIIECOG2501,JoanSchiller,MD.AStableDiseasePDDiscontinueProtocolTreatmentPRContinueNexavarprotocoltreatmentArm1NexavarpobidArm2PlacebopobidSCANRANDOMIZENexavar

pobidX2cycles(8weeks)PDPopulationStageIIIBandIV2ormorepriorchemotherapyregimens≥18yearsofageECOGPS0–1AsymptomaticbrainmetastasesallowedSampleSizeN=330accrued,98randomizedEndpoints1stendpoint:SDorresponseafter2coursesoftreatmentpostrandomization2ndendpoint:PFS,RR,SurvivalBSecond:Randomizedpatientsfirstevaluatedforprogressionafteranother8weeksFirst:PatientsevaluatedforSDat8weeksASCOAbstr8014.

Single-AgentNexavarin3rdli64EndpointOutcomeMeasuresRECIST/WHOResponseRateCR+PRCR+PR+SDTimetoFailure/SurvivalProgression-FreeRateDisease-FreeRateEndpointOutcomeMeasuresRECIS65EndpointOutcomeMeasuresBiologicalEndpointsSafety&AdverseEventsMultipleEndpointsQOLEndpointOutcomeMeasuresBiolo66CorrelativeStudiesImportant,hypothesis-generating,exploratorystudiesHowever,don’tdothembecauseeveryoneelseis…..BUTduringcourseofstudy:ValidationoftargetsandassaysmayoccurNewmarkersandpathwaysmaybeidentifiedConsidercollectingspecimenstoevaluateonlyifactivitysignalsareseeninstageI(for2-stagedesigns)CorrelativeStudiesImportant,67SampleSizeCalculationPriordeterminationofthesamplesizethatisneededtoshowanimportantdifferenceisessential.

Twoerrorscanbemadeinatestofahypothesis:rejectingthenullhypothesiswhenitistrue(TypeIError,)(false-positive)notrejectingthenullhypothesiswhenitisfalse(TypeII,)(false-negative).

AnotherimportantconsiderationisPower;theprobabilityofrejectingthenullhypothesiswhenitisfalse,orofconcludingthealternativehypothesiswhenitistrue.FromBasic&ClinicalBiostatisticsDawson-SaundersandTrappeds.SampleSizeCalculationPriord68SampleSizeCalculationBeforegoingtoyourstatisticianWhatisthedesiredlevelofsignificanceofthenullhypothesis(0)?Whatchanceshouldtherebeofdetectinganactualdifference(whatpower)associatedwiththealternativehypothesis(1)isdesired?Howlargeshouldthedifferencebetweentheproportions(1-

0)beinorderforittohaveclinicalimportance?Whatisagoodestimateofthestandarddeviationinthepopulation?ThevalueofthenullhypothesisdeterminesinmostcasesthestandarddeviationFromBasic&ClinicalBiostatisticsDawson-SaundersandTrappeds.SampleSizeCalculationBefore69N=Z0(1-0)-Z1(1-1)1-02SYSTAT,MINITAB,STATISTIXPASSN=Z0(1-0)-Z1(1-170Giventhiscomplexityofdesignandoutcomealternatives,theselectionofatrialdesignrequiresclosecollaborationbetweenthestudyinvestigatorandclinicalbiostatisticianstoclearlydefinestudyobjectives,toselectappropriateendpoints,toselectatrialdesign,andtocomputetherequirednumberofpatientstobeenrolled.

Weshouldindividualizethetrialdesignandoutcomemeasurestotheparticularagent(orcombination)anddiseaseorsubsetofdiseasetobeevaluated.Giventhiscomplexityofdesig71MyExamplesPhase2StudyofCapecitabineandDocetaxelinPreviouslyUntreatedadvancedNon-SmallCellLungCancerPatients(OSU-0356).NCIR21CA108157

Phase2trialofSequentiallyAdministeredCPT-11andMitomycinCinPatientswithAdvancedEsophagealandStomachCancer(OSU-0151).NCIR21CA92956Phase1/2StudyofEtanerceptandGemcitabineinPatientswithAdvancedStageandChemotherapy-NaïvePancreaticAdenocarcinoma(OSU-0041).NCIR21CA101360

MyExamplesPhase2StudyofCa72Phase2StudyofCapecitabine/DocetaxelinPreviouslyUntreatedAdvancedNSCLCPatientsCapecitabinelastconversionstepismediatedbythymidinephosphorylase(TF),whichispreferentiallyexpressedintumorsPreclinicalstudiessuggestthatpaclitaxel/docetaxelincreaseexpressionofTFAprevioustrialinpretreatedNSCLCpatients(n=31)showeda26%RR,25%26-wksPFS,MS9.1m,1-yearsurvival37%Phase2StudyofCapecitabine/73Howwouldyoudesignit?Simon2-stageMinimaxFleming1-stageRandomizedPhase2MickDesignRandomizedDiscontinuationHowwouldyoudesignit?Simon74InteractiveAnswerInteractiveAnswer75OurDesignEndpointRECISTobjectiveresponse(PR/CR)SimonTwo-stageminimax<30%nointerest,50%interestIf8ormorepatientsshowresponsesinthefirst28,11additionalpatientsaretreatedforatotalof39.If15showresponses,theregimenwillnotberecommendedforfurtherstudy.If16patientsshowresponsesinthe39,theregimenwillbestudiedfurther.

OurDesignEndpointRECISTobje76PotentialAlternatives?Fleming1-stage(yes,iftimedependentendpointswerechosen)RandomizedPhase2(yes,ifmulti-institutional)MickDesign(no,firstlinetreatment)RandomizedDiscontinuation(noforaggressivemalignancy,moreappropriatetotestdurabilityofefficacyorsignificanceofstability)PotentialAlternatives?Fleming77Phase2trialofSequentiallyAdministeredCPT-11andMitomycinCinPatientswithAdvancedEsophagealandStomachCancerIrinotecan(CPT-11)isatopoisomerase1(Topo1)interactiveagent.DecreasedlevelsofTopo1isamechanismofresistance

PreclinicalstudiesshowedthatmitomycinCupregulateactivityofTopo1,thusmodulationofTopo1activitybyMMCmayresultinincreasedresponsetoCPT-11MitomycinChasmanysideeffects,sodoctorshateit.AphaseItrialestablished6mg/m2onday1,followedbyCPT-11125mg/m2days2and9,every28daysassafe,andshowed5responsesinrefractoryesophagealcancerpatientsPhase2trialofSequenti