Abstract

Thecurrentlandscapeofoncologydrugdevelopmentisposingachallengetowidely-accepted methodsusedinearly-phaseclinicaltrials.AchallengeinPhaseItrialsofcancertreatmentis determiningarecommendedPhaseIIdose(RP2D)forfurthertestingofadoptivecelltherapies. Inthesetherapies,itmaynotbefeasibletoadministerapatient?sassigneddoseduetoan insufficientnumberofcellsharvestedorfunctionalheterogeneityoftheproduct.Thismakesit difficulttoidentifyafeasibledosetocarryforwardintomiddleandlatedevelopment,hindering theevaluationofthetherapeuticintervention.Accepteddosefindingdesignsweredeveloped foruseintrialsinwhichsuccessivepatientcohortsaretreatedatvariousdoselevelsthatare selectedbasedonthesafetydatafrompreviouscohorts.Thisapproachwasappropriateinthe historicalparadigminwhicheachpatientisabletoreceivehisorherintendeddosebasedon thedose-findingalgorithm.Inadoptivecelltherapy,thenumberofcellsproducedmaybebelow theassignedinfusiondoseidentifiedbythedose-findingdesignforagivenpatient.Thisraises questionsofhowtoassessthefeasibilityoftheapproach,whilealsoevaluatingsafety. Integratingaccumulatedfeasibilityandsafetydatatoselectsequentialdosesforpatientcohorts duringdose-findingtrialsremainsachallenge.Thereisneedtodevelopdosefindingdesignsfor adoptivecelltherapythatutilizefeasibilitydatainguidingallocationanddeterminingamaximum toleratedandfeasibledose(MTFD),leadingtomoreoptimaldosingandimprovedpatient outcomes.Theoverallgoalofthisproposalistodevelopdose-findingmethodologyforadoptive celltherapythatformallyintegratesdosefeasibilityintothedesign.

Public Health Relevance

PhaseIstudiesofnewtherapies,suchasadoptivecelltherapies,arebecomingincreasingly popularincancerresearch.Adoptivecelltherapyisapromisingcancertreatmentthatneeds evaluationbyproperlydesignedclinicaltrials.Anunmetneedistodevelopdosefindingdesigns foradoptivecelltherapythatutilizesafetyandfeasibilitydatainguidingallocationand determiningamaximumtoleratedandfeasibledose,leadingtomoreoptimaldosingand improvedpatientoutcomes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
5R03CA238966-02
Application #
9882242
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Timmer, William C
Project Start
2019-03-01
Project End
2021-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
University of Virginia
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904