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Finalanalysisofrelapse-freesurvivalinamulticenter,double-blind,placebo-controlledtrialofseviprotimut-Lpolyvalentmelanomavaccineafterresectionofhigh-riskmelanoma

CL.Slingluff Jr1, B Blumenstein2, K Lewis3, RHI Andtbacka4, JR Hyngstrom4, MM Milhem5, S Markovic6, O Hamid7, LF Hernandez-Aya8, TL Bowles9, P Philips10, S Jang11, J Lutzky12, A Bar13, P Beitsch14,. 1University of Virginia, 2Tri Arc Consulting, 3Anschutz Cancer Pavilion, 4Huntsman Cancer Institute, 5University of Iowa, 6Mayo Clinic Rochester, 7The Angeles Clinic, 8Washington University, 9Intermountain Medical Center, 10University of Louisville, 11Inova Medical and Skin Cancer Center, 12Mount Sinai Medical Center, 13Oregon Health and Science University, 14Dallas Surgical Group..

MethodsTheMelanomaAntigenVaccineImmunotherapyStudy(MAVIS)has3parts:PartA(n=99):40µgand100µgofseviprotimut-Lvsplacebo•  safety&biologicalactivity•  selectdoseforPartBbasedonimmune(antibody&T-cell)response.PartB1(n=325)seviprotimut-L40µgvsplacebo(2:1)•  recurrence-freesurvivalPartB2(n=800)seviprotimut-L40µgvsplacebo(1:1)•  survivalandrecurrence-freesurvivalco-primaryendpoints

ForMAVISPartB1,patientswithAJCCv7stageIIB-IIIcutaneousmelanoma,aftersurgicalresection,age18-75,ECOGPS0-1,wererandomized2:1toseviprotimut-L40mcgorplacebo,administeredintradermallyat4skinsitesevery2weeksx5,thenmonthlyx4,thenevery3monthstomonth24.

Patients were stratified by stage (IIB/C, IIIA, IIIB/C). Target enrollment was 325. The study was powered forassessmentofRFS,withtargethazardratio(HR)of0.625,one-sidedalpha0.10,power80%.Finaldataarepresented.

Endpointsaddressedinthisreport:PrimaryEndpoint:Recurrence-freesurvival(RFS);SecondaryEndpoints:IncidenceandseverityofAEs,overallsurvival(OS)

Results

Agecandecreaseimmunecompetence;thus,outcomeswereassessedbyage(<60and≥60),forallrandomizedpatients(Figure4A)andtheStageIIB/IICsubset(Figure4B).RFSwaslongerwithvaccine forallpatientsage<60 (N=191,HR0.64,95%CI [0.38,1.08])andamongstage IIB/Cpatients(N=52,HR=0.31,95%CI[0.12,0.84]).TheeffectmodificationpvalueforageforstageIIB/IICpatientswas0.56.

Conclusion

Acknowledgements

IntroductionManypatientswithresectedstageIIB-IIImelanomarelapseaftersurgery.ForStageIIB-Cpatients,the only FDA-approved treatment is high-dose interferon, which has limited effectiveness andfrequenttoxicity.Newtherapiesareneededforthesehigh-riskpatients.

Seviprotimut-L (formerly POL-103A) is an investigational, polyvalent melanoma vaccine thatcontainsmultiplemelanoma-associatedantigensthatareshedfrom3humanmelanomacelllines,admixedwithalumastheadjuvant.PriorformulationsshowedpromisingimmunogenicityforTcellandantibody responses.Anearlier formulationenhanced survival ina small randomizedphase IIclinicaltrialin38advancedstageIIImelanomapatients,inwhichtherecurrence-freesurvivalofthevaccine-treatedsubjectswasovertwicethatofplacebovaccine-treatedsubjects(p=0.03)[1].

PartB1ofMAVIS(MelanomaAntigenVaccineImmunotherapyStudy,athree-part,PhaseIIIclinicalprogram), was a multicenter, double-blind, placebo-controlled trial to assess the efficacy ofseviprotimut-L,with theprimaryendpointof relapse-freesurvival (RFS) inpatientsathigh riskofrecurrenceafterdefinitivesurgicalresection.

Seviprotimut-Ltreatmentiswell-tolerated.SubgroupefficacyanalysesidentifiedpopulationswhomaybenefitfromSeviprotimut-L:thosewithAJCCstageIIB/IICmelanoma,thoseunderage60,andthosewithulceratedmelanomas.ThesedatasupportproceedingtothedefinitivepartB2oftheMAVISphaseIIItrialtotestseviprotimut-LforstageIIB/Cpatients,withstratificationbyageandulceration.

WeacknowledgethesupportofallinvestigatorsandclinicalcoordinatorsresponsibleforenrollingpatientstothistrialandJean-ClaudeBystrynforhisinitialworkonthisvaccinestrategy.Registration:ThistrialwasregisteredatClinicalTrials.gov:NCT01546571.ThestudywasapprovedbytheEthicsBoardateachparticipatinginstitution.

ReferencesCited1.BystrynJC,Zeleniuch-JacquotteA,OratzRetal.Double-blindtrialofapolyvalent,shed-antigen,melanomavaccine.ClinicalCancerResearch2001;7:1882-1887.2.DorshkindK,SwainS.Age-associateddeclinesinimmunesystemdevelopmentandfunction:causes,consequences,andreversal.CurrOpinImmunol2009;21:404-407.

347subjectsat65centersintheU.S.andCanadawereenrolledandrandomized.Armswerewell-balanced(Table1).Treatment-emergentadverseevents(AEs)weresimilarforseviprotimut-Landplacebopatients: therewerenograde4-5treatment-relatedAEsandnotreatment-relatedSAEs(Table1).

Results(cont.)

B. RFS, by age & treatment, Stage IIB/C A. RFS, by age & treatment

Figure 1. Study schema

Figure 2. RFS by treatment

Figure 4. RFS by age and treatment

Byintent-to-treat(ITT)analysisoverall,RFSwasnotsignificantlyenhancedforseviprotimut-Lbuttrendedhigher(Figure2A).However,subgroupanalysisforplannedrandomizationstratumstageIIB/IICrevealedtrendstolongerRFS(HR0.65[0.37,1.17],Figure2B)&OS(HR0.37[0.13,1.06],Figure3)withvaccine.

Table1.Demographics,Enrollment,andadverseeventsSeviprotimut-L Placebo Total

N 230 117 347Age:Median(Q1,Q3) 58(48,67) 56(45,67) 58(47,67)Race:%White(Caucasian) 99% 100% 99%Sex:%female/%male 42%/58% 44%/56% 43%/57%Ethnicity:%HispanicorLatino 3% 3.4% 3.2%AEs 96% 97% 96%Grade3AEs 12% 9% 11%Rx-relatedAEs 70% 73% 71%AEsleadingtod/cstudydrug 0.9% 0.9% 0.9%Rx-relatedAEsleadingtod/cstudydrug 0.4% 0% 0.3%Rx=treatment

Table2.Demographics:StageIIB/CSeviprotimut-L Placebo

N 74 37Age:Median 60 61Sex:%female 35% 32%Race:%White 99% 100%Ethn:%Hispanic 4.1% 2.7%ECOGPS=0 86.5% 86.5%Tumorsite:Extremity/Head-neck/Trunk

34%/37%/26%

27%/32%/41%

A. RFS, all patients B. RFS, Stage IIB/C

Stage IIB/C patients were well-matched bytreatmentarms(Table2).

Figure 3. OS by treatment, Stage IIB/C

InamultivariableRFSmodel, theHRforthe38 IIB/IICpatients<60withulcerationwas0.209(95% CI [0.07,0.61]). The survival HR for the 191 patients <60 was 0.41 (19 deaths, 96% CI[0.33,1.14])andforthe156patients≥60,theHRwas0.92(24deaths,95%CI[0.39,2.12]).