Phase I clinical study of intratumoral injection of ......008-029 Sepsis Grade 4 Cohort 6 008-029...
Transcript of Phase I clinical study of intratumoral injection of ......008-029 Sepsis Grade 4 Cohort 6 008-029...
RESEARCH POSTER PRESENTATION DESIGN © 2015
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1 UTM.D.AndersonCancerCenter,Houston,TX77030,USA;2MemorialSloan-KetteringCancerCenter,NewYork, NY 10022,USA;3 WUSOMSitemanCancerCenter,St.Louis,MO;4 ClevelandClinic,Cleveland,OH;5BioMedValleyDiscoveriesInc.,KansasCity,MO64111,USA;6AtlasVenture,Boston,MA02139,USA
FilipJanku1,RaviMurthy1,AndreaWang-Gillam3,DaleShepard4,ThorunnHelgason1,TashaneHenry2,CharlesRudin2,StevenY.Huang1,DivyaSakamuri1,StephenBSolomon2,AmandaCollins5,BrentKreider5,MariaMiller5,SaurabhSaha5,6,DavidTung5,MaryVarterasian5,LinpingZhang5,HalleHZhang5,MrinalM.Gounder2
PhaseIclinicalstudyofintratumoralinjectionofoncolyticClostridiumnovyi-NTsporesinpatientswithadvancedcancers
BACKGROUNDIntratumoralinjectionofClostridiumnovyi-NT(C.novyi-NT),anattenuatedstrainofClostridium,inducedamicroscopicallyprecise,tumor-localizedresponseinaratorthotopicbraintumormodel,incompaniondogsbearingspontaneoussolidtumors,andinthefirstpatienttreatedonaPhase1humanclinicaltrial(Robertsetal,SciTranslMed.2014) 1.C.novyi-NTsporesgerminateinhypoxictumorenvironmentandlysemalignantcellsbysecretinglipases,proteases,otherhydrolyticenzymes,andrecruitinginflammatorycellstotumorselicitinganti-tumorimmuneresponsesinanimals2.Furthermore,intratumoralinjectioncanplausiblyinduceanimmunemediatedabscopaleffectinnon-injectedtumorsites.
METHODS
Study Design
Objectives• Todeterminethemaximumtolerateddose(MTD),anddose-limiting
toxicities(DLT)ofasingleintratumoral injectionofC.novyi-NTusingthestandard3+3doseescalationschedule
• Todocumentpreliminaryanti-tumoractivityofboththeinjectedtumorandanoverallresponse
• TostudythepresenceofcirculatingC.novyi-NTspores• TomeasurethehostimmuneandinflammatoryresponsetoC.novyi-
NTadministeredasasingleITinjectioninhumanswithtreatment-refractorysolidtumormalignancies
Majoreligibilitycriteria• Adultpatientswithadvancedsolidtumormalignancy• Targetedtumorhasalongestdiameter≥1cmand< 12cmandis
amenabletopercutaneousinjectionofC.novyi-NTspores.• Thetargettumormustnotbelocatedineitherthethoracic,
abdominal,pelviccavitiesorinthebrain.• ECOG0-2• ANC≥1,000/uL• Hemoglobin≥9g/dL• Platelets≥100,000/uL• Totalbilirubin≤1.5xupperlimitofnormal(ULN)• ALT/AST≤2.5xULN• INR≥1.3• Noprimarybrainmalignanciesorbrainmetastases• Noactiveinfectionortreatmentwithantibiotics
Intratumoral Injection
1Roberts,N,Zhang,L,etal.(2014).IntratumoralinjectionofClostridiumnovyi-NTsporesinducesantitumorresponses.SciTranslMed.6(249):249ra1112AgrawalN,BettegowdaC,etal.(2004)Bacteriolytictherapycangenerateapotentimmune responseagainstexperimentaltumors.ProcNatlAcadSciUSA101:15172-7
RESULTSDose Escalation
Patients Characteristics (n=21)
Best Response
Toxicity Data Summary
Tumor-specificT-cellResponse
CONCLUSION
DoseLevel
DoseofIntratumoralC.Novyi-NT
Spores
NumberofpatientsEnrolled Dose-limitingtoxicities(DLT)
1 1x104 3 None2 3x104 3 None3 10x104 4 None4 30x104 6 1(sepsis)
5 100x1043
Plannedcohortexpansionto6patientstodetermineMTD
None
6 300x104 22
(sepsis,gasgangrene)
Medianage– years(range) 55(29-75)
Male/Female 11/10
The Type, Location, Size, and Response of Injected Tumors
GreenFill:C.novyi-NT germination/tumordestruction*SAE
• Anti-canceractivitywasobservedin10outof21(48%)patientsinwhomC.novyi-NTgerminationresultedinextensive,insomecases,completecentralnecrosisoftheinjectedtumor.
• Twopatientshad22-24%shrinkageintheinjectedtumoratMonth1-2basedonRECISTassessment.Onepatienthas14%shrinkageintheinjectedtumoratMonth4.
• Outof the10patientswhowereevaluatedatMonth2,8patientshadanoverallresponseofstabledisease;2patientshadprogressivedisease.OnepatienthadstablediseaseatMonth4.
• Threeoutof21patientshadnovisiblesignsofC.novyi-NTgerminationbutexperienceddramaticclinicalimprovementatMonth1(Patient008-013)orslowedtumorgrowthatMonth2ascomparedwithtumorgrowthbeforeC. novyi-NTinjection(Patient011-028,008-026).
Baseline Day7
Patient008-029:65-year-oldmalewitha8.5x7cmmetastaticrightanteriorhipleiomyosarcoma.PatientwastreatedatDoseLevel6
(300x104 spores)
Baseline Day4
Patient011-019:75-year-olmalewitha3cmliposarcomaintherightinguinalnode.PatientwastreatedatDoseLevel4(30x104 spores).
• A singledoseofintratumoralinjectionofClostridiumnovyi-NTisfeasibleandhasledtosignificantdestructionofinjectedtumormasses.
• Stabilization/slowdownintumorgrowth innon-injectedmasseshasbeenobservedintwopatients.
• Thetolerabledosehasbeenexceeded,andexpansionofcohort5isplannedtodefineMTDandRP2D.
• APhaseIstudyofaPD1antibodywithC.novyi-NThasbeendesigned.
Patient011-001:53-year-oldfemalewitha7.6cmleiomyosarcoma intherightshoulderwithadjacenthumerus involvement.Patientwastreated
atDoseLevel1(1x104 spores).1
Day 4Baseline
Baseline:contrastenhancingmassinvolvingsofttissueandpossiblyadjacentbone.Lesionmeasuresabout7.2cmAPx7.4cmtransverseintheaxialdimensions.
Day4:markedlydiminishedcontrastenhancementwithinthetumormassofsofttissueandpossiblyadjacentbonecomponent
Day29:non-enhancingtumormassbecomesmorehomogeneousconsistentwithongoingnecrosis
Bay 29
Toassesstumor-specificT-cellresponsesinpatientstreatedwithC.novyi-NT injection,circulatingCD4andCD8cellswereisolatedfrompatient’sbloodandstimulatedwithpatient’sowndendriticcellswhichwerepulsedwithtumorantigens.ReleaseofT-cellcytokinesandeffectormoleculessuchasIFN-γ,granzyme-B,andTNF-α werequantifiedbyEnzyme-linkedImmuneAbsorbentSpot(ELISPOT)assays.
Most common adverse events (AEs) are hyperthermia/fever and tumorinflammation. Fever is expected due to the nature of the therapy andhas been observed in half of treated patients. Tumor inflammation andabscess events are generally considered desired mechanisms of C.novyi-NT treatment.
RelatedGrade3andAboveAEsandSeriousAdverseEvents(SAEs)
PatientID AdverseEvent Severity CohortDose
011-001 RespiratoryInsufficiency Grade3 Cohort1
011-001 PathologicFractureofRightHumerus Grade3 Cohort1
008-018 Sepsis Grade4 Cohort4
011-019 GenitalSwelling Grade2 Cohort4
011-023 Pain Grade3 Cohort4
011-023 Swelling Grade3 Cohort4
011-023 PossibleSkinInfection Grade3 Cohort4
011-027 Abscess Grade3 Cohort5
008-029 Sepsis Grade4 Cohort6
008-029 SoftTissueInfection Grade3 Cohort6
008-030 GasGangreneRightUpperExtremity Grade4 Cohort6
GreenFill:SAEs
P284
C.novyi-NT sporesareinjectedwithaneedleoralternateinjectiondevice,whichmaybe carriedoutunderradiographicguidance.Theinjectioncanberedirectedtomultipledistinctsitesinthetumortoachieveadequatedispersalofsporesthroughoutthetumor.
Patient Cohort TumorType Location Size(cm)
011-001 1 LeiomyosarcomaPeri-humerusSoftTissue(right)
7.6*
011-002 1 Chondrosarcoma SQChestWall(Left) 2.7
011-003 1 Leiomyosarcoma SQAbdominalWall(Left) 2.6
011-004 2 MullerianCarcinoma SQleftflank 10.5
008-006 2 Angiosarcoma SQnecklymphnode 2.8
011-007 2 PapillarythyroidCarcinoma SQScapularLesion 3
006-010 3 Breastcancer SkinLesion 3(DuctalCarcinoma)
008-012 3Serous Ovarian
AxillaryMass 5Cystadenocarcinoma
008-013 3OropharyngealCancer(HPV-relatedSquamous
CellCarcinoma)
Pre-auricularLymphNode 2
011-014 3BreastCancer LeftChestWall
3(TripleNegativeadenocarcinoma)
SuperficialLesion
011-016 4 leiomyosarcoma RightAbdominalWall 5
008-018 4 MetastaticOsteosarcoma RightLegAmputationSite 8*
011-019 4 Liposarcoma RightGroin 3*011-021 4 EndometrialCarcinoma AbdominalWall 3
003-022 4 Sarcoma Left Lateral AbdominalWall 3.7
011-023 4 Adenocarcinoma Axilla 10
008-026 5 Chordoma ChestWall(LeftPosterior) 2.8
011-027 5 SpindleCellSarcoma RightArm 4.5*011-028 5 NRAS-mutatedMelanoma AbdominalWall 2.5
008-029 6 Leiomyosarcoma RightAnteriorHip 8.5*
008-030 6 Myxofibrosarcoma Bicep 10*