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EstablishtheMaximumToleratedDoseinPhase-ITrialsusing3+3Method
Anup PillaiCytel,Pune,India
Vienna11th - 14th October2015
21October2015 1SP04PhUSE 2015
Ø Introduction to Phase-1 trials
Ø Dose Escalation Studies
Ø 3+3 design for findingMaximum Tolerated Dose
Ø Case Study for findingMaximum Tolerated Dose
Ø SAS® Macro for Simulating 3+3 Design
Ø Limitations of 3+3 Design
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Agenda
PhasesofaClinicalTrialInitialtestingdone inlaborwithanimals
Phase- IV
Find thesafestdoseFindmosteffectivewaytoadministeradose
ConfirmatoryPhase
CheckingforSafetyandEffectiveness
PostMarketingSurveillance
21October2015 3SP04PhUSE 2015
Phase- III
Phase- II
Phase- I
PreClinical
Phase-ITrials
Aim MaximumToleratedDose(MTD)
Thehighestdoseofatreatmentthatdoesnotcauseunacceptablesideeffects.
MTD
DoseLimitingToxicity.Unacceptablesideeffectsortoxicity.
DLT
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Phase-ITrials
• Phase-Itrialsarefirsttrialsconductedonhumans.
• Usuallythesetrialsincludehealthyvolunteers.Buttherearecircumstanceswhenrealpatientsareused,suchasoncologytrials.
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• Anincreaseddoseisassociatedwithincreasedchanceofclinicalefficacy.
• PhaseItrialsaredesignedasadose-escalationstudytodeterminetheMTD.
Phase-ITrials
Dose
Respon
se
Efficacy
Toxicity
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DoseEscalationStudies• Minimize the number of patients exposed to toxic doses,
while identifyingthe MTD.
• Dose escalation methods fall into two broad classes:– Rule Based Design– Model Based Design
• Rule-based designs allow dose escalation and de-escalationdepending on the absence or presence of DLTs in the previouscohort of treated subjects.
• The most widely used rule based design is the 3+3 design.
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Treat3SubjectsonStartingDosei
Enroll3moreSubjectsonDosei
0DLT >1DLT1DLT
EscalatetoDosei+1
De-escalatetoDosei-1
1/6DLT >1/6DLT
3+3DesignAlgorithmofatraditional3+3Design
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CaseStudy• A study was conducted to determine the MTD of HB-110, a
vaccine administered by Electroporation in chronic hepatitis Bpatients.
• The 3+3 design was used to reach the MTD.– Subjects were observed for a minimumof 28 days.– Each subject was administered HB-110 per day.
• The dose-levels of HB-110 used were 1mg, 2mg, 4mg & 6mg.
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SubjectID
DoseLevel(m
g)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
6
4
2
1
DLT
MTD
PerSubjectResponseinthetrial
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CaseStudy
NoDLT
SubjectID
DoseLevel(m
g)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
6
4
2
1
DLT
UnabletofindtheMTD
21October2015 11SP04PhUSE 2015
CaseStudy
NoDLT
MTDbelowLowestDose
SubjectID
DoseLevel(m
g)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
6
4
2
1
DLT
UnabletofindtheMTD
21October2015 12SP04PhUSE 2015
CaseStudy
NoDLT
MTDaboveHighestDose
%MTD_3x3(treatment=1,no_sim =1000,sample_siz =30);
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SASMacroThemacrosimulatesa3+3Design
SerialNumber
DoseValue Probabilityofobserving aDLT
StartingDose Numberof simulations MaximumSampleSize
Inputdataset:‘dose_escalation’
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SASMacro
Outputdataset:‘Simulation_summary’
• Thedesignisinflexible.
• Decisionsarenotbasedonoutcomesfromallrecruitedsubjects.
• ManysubjectsaretreatedatdoseslowerthanMTDwhilefewsubjectsactuallyreceivetheMTD.
TheselimitationsareovercomebymodelbaseddesignslikeCRM(ContinualReassessmentMethod)BLRM(BayesianLogisticRegressionMethod)
21October2015 15SP04PhUSE 2015
Limitations
• 3+3 remains the most popular method because of its simpleconcept and operational ease.
• It can be implemented without any complex statisticalconsiderationsand computations.
• 3+3 design is used as a starting step for carrying out morecomplex designs.
Summary
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21October2015 SP04PhUSE 2015 17
ReferencesLeTourneau,Christophe,J.JackLee,andLillianL.Siu."Doseescalationmethods inphaseIcancerclinicaltrials."JournaloftheNationalCancerInstitute (2009).
Storer,BarryE."DesignandanalysisofphaseIclinicaltrials."Biometrics(1989):925-937.
Neuenschwander,Beat,MichaelBranson,andThomasGsponer."CriticalaspectsoftheBayesianapproachtophaseIcancertrials." Statisticsinmedicine 27.13(2008):2420-2439.
Thall,P.F.,andS-J.Lee."Practicalmodel-baseddose-finding inphaseIclinicaltrials:Methodsbasedontoxicity." InternationalJournalofGynecologicalCancer 13.3(2003):251-261.
Zohar,Sarah,andSylvieChevret."Thecontinualreassessmentmethod:comparisonofBayesianstoppingrulesfordose-rangingstudies." Statistics inmedicine 20.19(2001):2827-2843.
O'Quigley,John,MargaretPepe,andLloydFisher."Continualreassessmentmethod:apracticaldesignforphase1clinicaltrialsincancer."Biometrics(1990):33-48.
CaseStudy:“Tolerability,ImmunogenicityandEfficacyofHB-110AdministeredbyElectroporationinChronicHepatitisBPatients.”https://clinicaltrials.gov
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