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