Oncology phase I study dose escalation methods

OncologyPhaseIClinicalTrialDesignsandChallengesCRATrainingSession18Oct2013TableofContentsGeneralIntroductionofPhaseIStudyTermsandDefinitionsDoseEscalationStudyDesignandChallenges–TraditionalDesign–ContinualReassessmentMethod(CRM)GeneralDesignConsiderations–Choosingdose–DefiningDLTQuestionsandAnswersSessionGeneralIntroductionofPhaseIStudyClinicalTrialPhasesPhaseNumberandSubjectTypeAddressingQuestionsI50−200healthysubjects(usually)orpatientswhoarenotexpectedtobenefitfromtheIMP•IstheIMPsafeinhumans?•WhatdoesthebodydototheIMP?(pharmacokinetics)•WhatdoestheIMPdotothebody?(pharmacodynamics)•MighttheIMPworkinpatients?II100−400patientswiththetargetdisease•IstheIMPsafeinpatients?•DoestheIMPseemtoworkinpatients?(efficacy)III1000−5000patientswiththetargetdisease•IstheIMPreallysafeinpatients?•DoestheIMPreallyworkinpatients?IVmanythousandsormillionspatientswiththetargetdisease•Justhowsafeisthenewmedicine?(pharmacovigilance)•Doesthemedicineworkintherealworld?(realworlddatacollectedtodemonstratevalue)•Howdoesthenewmedicinecomparewithsimilarmedicines?PhaseIIntroductionAPhase1studyisdefinedasanon-therapeutic,exploratorytrialinhumansubjectswhomaybehealthyorhaveaspecificdisease.Incontrasttolaterphasestudies,subjectscanusuallyexpectnotherapeuticbenefitfromaPhase1trial.TheprimaryparameterstestedinPhase1studies(whichcaninvolvesingleormultipledosesoftheIMP)are:•Safetyandtolerability•Pharmacokinetics•PharmacodynamicsTypesofPhaseIstudiesThereisarangeofdistinctPhase1studies,eachofwhichisdesignedtoaddressaparticularquestionorsetofquestions:First-in-HumantrialThefirsttrialofanIMPinhumansisusuallyatrialofsingledosesgiveninincreasingamounts.Theaimsaretoassessthetolerability,safety,pharmacokineticsand,ifpossible,thepharmacodynamiceffectsoftheIMP,andtocomparetheresultswiththosefromthepreclinicalstudies.Subsequenttrials(examples)•theeffectsofpotentialinfluences,suchasfood,gender,ageandgeneticdifferences,ontheactivityoftheIMP•therelationshipbetweendoseorconcentrationoftheIMPandtheresponse•thepossibleinteractionoftheIMPwithmarketedmedicines•theabsorption,distribution,metabolismandelimination•thebioavailabilityorbioequivalenceoftheIMP•theeffectoftheIMPontheQTintervaloftheelectrocardiogram(ECG)TermsandDefinitionsTermsandDefinitions–Safety,ToxicityandTolerability–Doselimitingtoxicities(DLT)–MaximallyAdministeredDose(MAD)–MaximallyToleratedDose(MTD)–RecommendedPhaseIIdose(RP2D)–DoseEscalationRules–PharmacokineticsandPharmacodynamicsSafety,ToxicityandTolerabilityStandardtoxicityassessmentbyCommonTerminologyCriteriaforAdverseEvents(CTCAE)•Grading:0-5•CausalitydeterminationExample:ToxicityAssessmentPresentation:A47yearoldCaucasianmalestartsaninvestigationalagenton1Apr2011,Fourdayslaterhepresentswithanewrashoverhisentirerightarmwithitching.Hecontinuestohavemildfatigue,butnowhasanunquenchablethirst.Heisabletodohisdailychores.Hisfastingbloodglucoseis271mg/dL.BaselinecriteriaincludedGradeIfatigue,butotherwisenosymptoms.Assessment:GradingandRelatedness(CTCAEIPhoneApp,or(ctep.cancer.gov/protocoldevelopment/electronic.../ctcaev4.03.pdf)Fatigue:Rash:FastingBloodGlucose:CTCAESOC–Metabolic/LaboratoryCTCAESOC–Dermatology/SkinExample:ToxicityAssessmentPresentation:A47yearoldCaucasianmalestartsaninvestigationalagenton4-1-11,Fourdayslaterhepresentswithrashoverthearmsandchest,fatigue,andunquenchablethirst.Heisabletodohisdailychoresandhasotherwisenosymptoms.Hisfastingbloodglucoseis271.BaselinecriteriaincludedGradeIfatigue,butotherwisenosymptoms.Assessment:Fatigue:Grade1,notrelatedRash:Grade2,relatedFastingBloodGlucose:Grade3,relatedDLTDoselimitingtoxicities(DLT)withinwindow(usually3-4weeks)–Grade3non-hematologicaltoxicities–Grade4hematological–Protocol-specificdefinitions•E.g.allowforgrade3–Diarrheadespiteoptimalcare,–Nauseadespiteoptimalcare–Hyperglycemia(withtreatmentformorethan14days)(PI3k,mTOR)–Hypertension(VEGFinhibitors,VEGFRinhibitors)MAD,MTD,DoseEscalationRules,RP2D–MaximallyAdministeredDose(MAD)•Highestadministereddose(2/6ptswithDLT)–MaximallyToleratedDose(MTD)•Highesttesteddosewhere0/6or1/6patientsexperiencedDLT–DoseEscalationRules•Pre-definedconditionsfordoseescalation(standardandspecifictotheindividualprotocol)–RecommendedPhaseIIdose(RP2D)•ThedosetobetestedinphaseIIPharmacokineticsTARGETSITE(Receptor)FreeDrug↕BoundDrugTISSUESITEFreeDrug↕BoundDrugMetabolismEliminationExcretionPolymorphismPharmacokinetics“DrugBehaviorintheSubject”FreeDrugPlasma↕MetabolitesBoundDrugAbsorptionP.MunsterADMEAbsorptionDistributionMetabolismEliminationRoutinelydone:•Half-life(t1/2)•Distributionvolume•Peakconcentrations(Cmax)•Timetopeakconcentration(Tmax)•AreaUndertheCurve(AUC)•FoodeffectsNotroutinelydone:•Polymorphisms•Drug-druginteractions•PK-PDinteractionsPharmacokineticsMeasurablesPharmacodynamics“DrugEffectsonthesubjectsandtumors”•Symptoms•Signs•ChangesinLabvalues(e.geffectsonglucosemetabolism)•MolecularandBiologicaleffectsDoseEscalationStudyDesignandChallengesCancerPhaseI-DosefindingTraditionalgoal:•FindthehighestdosewithacceptabletoxicityNewgoals:•Finddosewithsuffi