CombinationofSelinexor withHigh-DoseCytarabineandMitoxantroneforRemissionInductioninAcuteMyeloidLeukemiaisFeasibleandTolerable– APhaseIStudy
(NCT02573363)AmyY.Wang,HowieWeiner,MargaretGreen,RichardA.Larson,Olatoyosi Odenike,AndrewArtz,LucyA.Godley,MichaelJ.Thirman,JaneE.Churpek,EmilyCurran,Kristen
Pettit,WendyStock,HongtaoLiu12/3/2016,AmericanSocietyofHematology
Disclosure
• StudywassponsoredbyKaryopharm Therapeutics• Nofinancialrelationshipstodisclose• Otherdisclosures:
Hongtao Liu,MD(PrincipalInvestigator)• Consultantfor:MedImmune/AstraZeneca,Pfizer,Novartis• Grant/Researchsupportfrom:Karyopharm Therapeutics,BMS• Honorariafrom:Alexion
Background
• Acutemyeloidleukemia(AML)isadiseasewithpoorprognosis• Standardinductionchemotherapyregimeninvolvescombinationofcytarabine withanthracycline
• High-dosecytarabine(HiDAC)withmitoxantrone(Mito)isfrequentlyusedatU.Chicagowithgoodresponserates– HiDAC/MitoinhighriskAMLpatients:OverallResponseRate(ORR)of55%(Larsonetal.,2012)
– HiDAC/Mitoinuntreatedtherapy-relatedmyeloidneoplasms:ORR82%(Godleyetal.,2010)
Selinexor:NovelOralAnti-CancerAgentRestoresTumorSuppressors&ReducesOncoproteins
©2016Karyopharm TherapeuticsInc.
• Selinexor(KPT-330)isaselectiveinhibitorofnuclearexport(SINE™)thatinhibitsexportin1(XPO1)
• Mechanism1:NuclearRetentionandActivationofTumorSuppressorProteins
• Mechanism2:ReductionofOncoproteinsThroughNuclearRetentionoftheirmRNAs
• Mechanism3:InhibitionofDNAdamagerepair
SelinexorisTolerablewithAnti-LeukemicEffects• AphaseIstudyofselinexormonotherapyinrelapsed/refractoryAMLshowedthatitiswell-
toleratedandefficacious1,2• Karyopharm’s PhaseIItrial(SOPRA)usingsingle-agentselinexorinpatientswithrelapsedAMLis
closetofullenrollment• 60mgselinexor flatdosingtwiceweekly(RP2D)
• Otherclinicaltrialsthatcombineselinexor withcytarabine-basedregimensshowfavorablesafetyandefficacyprofiles(NCT02403310,NCT02249091)
• Treatmentwithselinexor andtopoisomeraseIIinhibitors(e.g.Idarubicin)demonstratedtherapeuticsynergyrecently3
1Garzonetal.,Blood,2013. 2Yeeetal.,JClinOnc,2014. 3Ranganathanetal.,ClinCancerRes,2016.
WehypothesizedthataddingselinexortoHiDAC/Mitoisfeasibleandhassynergisticanti-leukemiceffects.
PhaseIStudyDesign
INDUCTION
• Selinexor(Days2,4,9,11)
• High-doseCytarabine(Days1,5)
• Mitoxantrone(Days1,5)
InCR CONSOLIDATION
• Selinexor(Days2,4,9,11)
• High-dosecytarabine(Days1,3,5)
• Upto4cycles
MAINTENANCE
• Selinexorweekly
• Uptototal1year
SCREENING
REGISTRATION
NotinCR OFFSTUDY
• Open-label,doseescalationofselinexor withexpansioncohort– 3+3design– 60mg(35mg/m2)and80mg(50mg/m2)
(Orproceedtoallo-SCT)
References:KCP-330-001,KCP-330-002,KCP-330-003
StudyObjectives• PrimaryObjective– TodeterminetheMaximumToleratedDose(MTD)ofselinexor tocombinewithHiDAC+mito
• SecondaryObjectives– TodeterminetheCompleteRemission(CR)ratefollowinginductionchemotherapy
– Todeterminethetoxicitiesofthecombinationregimenduringinduction,consolidation,andmaintenance
– TodeterminetheRelapse-freeSurvival(RFS)andOverallSurvival(OS)ratesduringconsolidationandmaintenancetreatment
– TodeterminetheStemCellTransplantation(SCT)successrate
KeyEligibilityCriteria• Approximately27patientstobeenrolled• Inclusioncriteria:
– Newlydiagnosedorrelapsed/refractoryAMLpatientssuitableforintensivetherapy
– LVEF>50%– ECOGperformancestatus≤2– Meetslaboratorycriteriaforrenalandhepaticfunction
• Exclusioncriteria:– Treatmentwithanyinvestigationalagentwithin2weeks– AMLwithCNSinvolvement– Significantco-morbiditiesthatcouldcompromisepatient’ssafety
PatientCharacteristics(asofNov2016)PatientCharacteristics Number(%)
Total PatientsEnrolled 20
Selinexor 60mg 3
Selinexor 80mg 17
#Female 14(70%)
Medianage 61(range44-76)
InitialAMLDiagnosis
DenovoAML 12(60%)
SecondaryAML 8(40%)
Diseasestateon enrollment
NewlydiagnosedAML 12(60%)
Relapsed/Refractory(R/R)AML 8(40%)
Median# ofpriorregimens (R/Ronly) 1.5(range1-3)
EuropeanLeukemiaNet riskgroup
Favorable 4(20%)
IntermediateI/II 8(40%)
Adverse 8(40%)
19/20patientsareevaluableforsafetyandefficacy,asof11/15/2016
DefinitionofDLT• DoseLimitingToxicity(DLT)– Observationperiod:upto56days– Anygrade3*orgreatertreatment-related,non-hematologictoxicity,except• Transient(<48hours)nausea/vomitingandliverfunctionabnormalities• Electrolyteabnormalitiescorrectablewithsupportivetherapy
– Persistentbonemarrowaplasialasting>56daysintheabsenceofdisease
– DLTswerenotevaluatedinpatientsenrolledindoseexpansion
*GradedaccordingtotheNationalCancerInstituteCommonTerminologyCriteriaforAdverseEvents(NCICTCAE)4.03
NoDLTsWereObservedDuringDose-Escalation
• NoDLTsbasedonprotocoldefinition– 1patientinexpansioncohorthadaplasticmarrowbeyondday56;however,shehadpre-existinghypocellular marrow
– 1patientinexpansioncohortdiedduringinductionofhemorrhagicstrokewithaplateletof4K
• RP2D:Selinexor80mg+HiDAC+mitoxantrone
Non-HematologicAdverseEvents
1Larsonetal.,2012
*= Serious Adverse Events (5/19 = 26%)#= 64% in HiDAC+mitoxantrone (Larson et al., 2012)&=Intracranial bleeding after 2nd selinexor dose on day 4 of induction
AdverseEvents Total Grade1&2 Grade3 Grade 4 Grade5Febrile neutropenia 14 (74%) 0 14 (74%)# 0 0Diarrhea 6 (32%) 6 (32%) 0 0 0Anorexia 5 (26%) 5 (26%) 0 0 0Electrolyte abnormalities 5 (26%) 5 (26%) 0 0 0Bacteremia 5 (26%) 0 5 (26%) 0 0Nausea/vomiting 4 (21%) 4 (21%) 0 0 0Fatigue 4 (21%) 4 (21%) 0 0 0Typhlitis/colitis 4 (21%) 3 (16%) 1 (5%) 0 0Cardiac toxicity 4 (21%) 2 (11%) 2 (11%) 0 0Alopecia 3 (16%) 3 (16%) 0 0 0Line-associated DVT 3 (16%) 0 3 (16%) 0 0Pneumonia 2 (11%) 0 2 (11%) 0 0Syncope/Pre-syncope 2 (11%) 1 (5%) 1 (5%) 0 0Hypoxia 1 (5%) 0 1 (5%) 0 0Urinary tract infection* 1 (5%) 0 1 (5%) 0 0Cerebellar toxicity* 1 (5%) 0 1 (5%) 0 0Hemorrhagic stroke* 1 (5%) 0 0 0 1 (5%)&
Cellulitis* 1 (5%) 0 1 (5%) 0 0Endocarditis* 1 (5%) 0 1 (5%) 0 0Diverticulitis 1 (5%) 1 (5%) 0 0 0Total 68 34 33 0 1
Selinexor+HiDAC/MitoisTolerable
• Themostcommonnon-infectiousadverseeffectswereallGrade1or2andmanageablewithsupportivecare– Diarrhea,anorexia,electrolyteabnormalities,nausea/vomiting,fatigue
• 19/20patientscompletedinductiontherapy– 1inductiondeath– Allrespondingpatientswentontoconsolidationorstemcelltransplant
ResponseRatesbySelinexorDose
DoseLevel #PatientsEvaluatedResponse
TF CR CRi PR ORR60mg 3 2 1 0 0 180mg 16 4 8 3 1 12
Total 19 6(32%)
9(47%)
3(16%)
1(5%)
13(68%)
CR=completeremissionCRi =remissionwithincompletecountrecoveryPR=partialremissionORR=overallresponserateDLT=doselimitingtoxicityTF=treatmentfailure
ORR=13/19=68.4%CR/CRi rate=12/19=63%
SubgroupResponseRatesCR CRi PR TF Total ORR
AML RiskNewlydiagnosed 6(55%) 3(27%) 1(9%) 1(9%) 11 10(91%)Relapsed/Refractory 3(38%) 0 0 5(63%) 8 3(38%)
European LeukemiaNet RiskGroupFavorable 3(100%) 0 0 0 3 3(100%)Int I/II 3(38%) 2(25%) 0 3(38%) 8 5(63%)Adverse 3(38%) 1(13%) 1(13%) 3(38%) 8 5(63%)
AgeAge>60 3(33%) 2(22%) 0 4 (44%) 9 5(56%)Age≤60 6(60%) 1 (10%) 1(10%) 2(20%) 10 8(80%)
Patient#2• Female• Selinexor
60mg• Denovo• Adverse
risk• Achieved
CR
ReductionofDNADamageResponseProteinandNuclearLocalizationofP53bySelinexor
Conclusions
• CombinationofSelinexorwithHiDAC/MitoxantroneiswelltoleratedwithRP2Dofselinexorat80mg
• ThemostcommontoxicitiesincludedfebrileneutropeniaandGI-relatedtoxicities,suchasanorexia,diarrhea,andnausea.
• SelinexorwithHiDAC/MitoxantronehasapromisingORRof68%outof19patients,aswellasanORRof91%inpatientswithnewlydiagnosedAML
• Thecombinationofselinexor +HiDAC +mitoxantronewarrantsfurtherinvestigationinalargerstudy
Acknowledgements• Wearesincerelygratefulforthesupportof:– KaryopharmTherapeutics– UniversityofChicagoLeukemiaProgram– Patientsandallthestaffinvolvedinpatientcare
• MyMentor:Dr.HongtaoLiu• SupportbyHowieWeiner• ThefundingsupporttoDr.HongtaoLiu:
– UCCCC-programgrant– CancerResearchFoundation– K12PaulCalabresi Award Dr.HongtaoLiu
Post-inductionOutcomes
• 4totaldeaths– 2TFwithprogressionofdisease– 1relapseafterremissionx5months– 1inductiondeath
• Post-inductionplanforthoseinremission:– 6haveundergoneallogeneicSCT– 4wentontoconsolidation– 2areplanningforSCT– 1awaitingforcountrecovery
TreatmentHistory
PriorTreatment Number (%)Untreated 12(60%)1st relapse 3(15%)Beyond1st relapse 1(5%)Primary refractory 4(20%)Priortherapies • Combinationcytarabinewithanthracycline
• HiDAC• Hypomethylatingagents(eg. Decitabine)• Tyrosinekinaseinhibitors• FLAG-IDA• ATRA• Clinicaltrialagents
Results
• MediantimetoCR:35days–WithG-CSF:31days–WithoutG-CSF:37.5days
Post-InductionOutcomesPatientID Diagnosis Selinexor Dose Response Outcome
1 De novo 60mg TF Offstudy
2 Denovo 60mg CR Inconsolidation
3 Refractory 60mg TF Offstudy
4 Relapsed 80mg TF Offstudy;died ofdiseaseprogression
5 Denovo 80mg CR Inremissionfor 5monthsbeforerelapse;diedofdiseaseprogression
6 Refractory 80mg TF Offstudy
7 Denovo 80mg CR Allo-SCT
8 Denovo 80mg CRi Earlyrelapse,thendecitabinebridgetoallo-SCT
9 Denovo 80mg PR Selinexor bridge toallo-SCT
10 Denovo 80mg CR Sorafenib bridgetoallo-SCT
11 Refractory 80mg CR Allo-SCT
12 Denovo 80mg CRi Allo-SCT
13 Relapsed 80mg CR In consolidation
14 Denovo 80mg CR Inmaintenance
15 Denovo 80mg CRi Awaitingcountrecovery
16 Relapsed 80mg TF Offstudy
17 Denovo 80mg CR Inconsolidation,planningforallo-SCT
18 Refractory 80mg CR In consolidation,planningforallo-SCT
19 Relapsed 80mg TF Offstudy;diedduringinductionofhemorrhagic stroke
20 Denovo 80mg Pending n/a
