Safety,Efficacy,andDetermina2onoftheRecommendedPhase2DosefortheOralSelec2veInhibitorofNuclearExport(SINE)

Selinexor(KPT-330)Chris&ne Chen1, Ramiro Garzon2, Mar&n Gu&errez3, Megan Jacoby4, PeterBrown5, Ian Flinn6, Richard Stone7, Lynn Savoie8, RachidBaz9,NashatGabrail10,MichaelWang11,PeterMar&n12,DavidSeigel3,MortenMau-Sorensen5,MichaelAndreeff11, Tracey Marshall13, Jean-Richard Saint-Mar&n13, Robert Carlson13,SharonShacham13,MichaelKauffman13,JohnKuruvilla1

(1) Princess Margaret Cancer Center, Toronto, Canada; (2) The Ohio State University, James CancerHospital, OH, USA; (3) John Theurer Cancer Center, Hackensack, NJ, USA; (4) Washington UniversitySchoolofMedicine,St.Louis,MO,USA;(5)Dept.ofOncology,Rigshospitalet,Copenhagen,Denmark;(6)Sarah Cannon Research Ins&tute, Tennessee Oncology, Nashville, TN, USA; (7) Dana-Farber CancerIns&tute,Boston,MA,USA;(8)UniversityofCalgaryDivisionofHematology,Calgary,Canada(9)H.LeeMoffi`CancerCenter&ResearchIns&tuteInc.,Tampa,FL,USA;(10)GabrailCancerCenter,Canton,OH(11)MDAndersonCancerCenter,Houston,TX,USA; (12)WeilCornellMedicalCollege,NewYork,NY,USA;(13)KaryopharmTherapeu&csInc,Newton,MA,USA

Disclosures

2

ResearchSupport Celgene,Sanofi

Consultant NA

Honoraria Celgene,Janssen,Lundbeck,Amgen,GSK

Scien2ficAdvisoryBoard NA

MajorStockholder NA

Employee,SpeakersBureau NA

SelinexorMechanismofAc2on•  XPO1 is a nuclear export protein thattransports protein cargos from thenucleustothecytoplasm

•  XPO1 isover-expressed inmanycancers,includinghematologicmalignancies

•  Selinexor is a Selec2ve Inhibitor ofNuclearExport (SINE) that inhibitsXPO1,forcing nuclear reten2on of tumorsuppressorproteins(TSPs)andotherkeyregulatorsofcancergrowthandsurvival

•  Keyan2-cancereffects:–  Nuclear reten2on and reac2va2on of TSPs (e.g.

p53,BRCA1/2,Rb)andIκB–  Blockade eIF4e-mediated transport of mRNAs

leading to decreased oncoprotein expression(e.g.c-Myc,Bcl-2/6)

3

XPO1

Inducednuclearreten2onofTSPsandoncogenemRNAs

4

(A)Selinexor(1μM)inducednuclearreten2onoftumorsuppressorp53andNF-κBinhibitorIκBincellculturea_er4h

p53

vehicle selinexor

IκB

C

(B)And(C)Selinexor(0.5μM)inducednuclearreten2onofmRNAforMYCandBCL6andreducedtheirproteinexpressiona_er24hinDLBCLcelllines(Marulloetal.CancerResAugust1,201575;LB-062)

A B

•  Phase1doseescala2onandexpansionstudyofselinexorinpa2entswithadvancedhematologicalmalignancies

•  Primaryobjec2vestoevaluatesafetyandtolerabilityofselinexoranddeterminetherecommendedPhase2dose(RP2D)

•  SecondaryObjec2vestoevaluatePK,PDandefficacy

• MainInclusionCriteria–  Pa2ents≥18yearsold,ECOGperformancestatus0-1,noavailable

standardtreatments–  ANC>1000/µL,Platelets>30,000/µL–  Documenteddiseaseprogressionatstudyentry

Phase1studyoverview

5

6

SelinexorPhase1studyarms

HematologicMalignancies(n=77)ARM1

3-80mg/m2(4,6,8or10doses/28dcycle)

ARM2AcuteMyeloidLeukemia(AML,n=71)

17-70mg/m2(4,8or10doses/28dcycle)

ESCALATIONS

30-60mg/m2;30or60mgflat(8doses/cycle)

40mg/m2,8doses/cycle

ARM6

ARM7

Mul2pleMyelomaSEL-DEX(MM,n=25)

Non-Hodgkin’sLymphomaSEL-R(NHL,n=19)

45,60mg/m2+20mgdexamethasone,8doses(combo)/cycle

45mg/m2(6doses/cycle)+375mgrituximab(1dose/cycle)

EXPANSIONS

NHL/CLL(n=32),MM/WM(n=23)

AML(n=24)

COMBINATIONS

ARMS3-5expansionsincluded14pa&ents(6TCL,1CML,7ALL),30-40mg/m2,8doses/cycle

Pharmacokine2candpharmacodynamicstudies

7

1 10 10010

100

1000

selinexor (mg)

C max

(ng/

mL)

Cmax vs mg dose

r2 = 0.60

n =109

1 10 10010

100

1000

selinexor (mg/m2)

C max

(ng/

mL)

Cmax vs mg/m2 dose

r2 = 0.68

n =109

1 10 100100

1000

10000

selinexor (mg)

AUC 0-

48 (h

*ng/

mL)

AUC vs mg dose

r2 = 0.63

n =105

1 10 100100

1000

10000

selinexor (mg/m2)

AUC 0-

48 (h

*ng/

mL)

AUC vs mg/m2 dose

r2 = 0.78

n =105

•  Pharmacokine2csshowedsimilarCmaxandAUCwithBSA-based(3-80mg/m2range)orflatdosing(4-175mgrange)

•  Pharmacodynamicstudiesshowedsustainedresponse>48hrs

AUCCmax

•  Supportsflatdosingonanintermipentschedule

8

SelinexorPhase1Demographics

*doesnotincludeNHLrituximabcombina2onptsinArm7

Pa2entanddiseasecharacteris2cs N=266*MedianAge(Range) 64(23-89)

AcuteMyeloidLeukemia(AML)

No.ofpa2ents 95Medianpriorregimens(range) 3(0-8)Cytogene2cRisk(Good/Intermediate/Poor) 14/25/30Flt3mutated 11

Non-Hodgkin'sLymphoma(NHL)

No.ofpa2ents 66*Medianpriorregimens(range) 4(1-12)DLBCL(Total/transformed/doublehit) 30/12/6Richter'sTransforma2on 8

Mul2pleMyeloma(MM)/Waldenstrom's

macroglobulinemia(WM)

No.ofpa2ents 81/3Medianpriorregimens(range) 6(1-16)ProteasomeinhibitorandIMiDrefractory 62Bortezomib,carfilzomib,lenalidomideandpomalidomideexposed 30

ALL/CLL/TCL/CML No.ofpa2ents 7/7/6/1

ADVERSE'EVENTS Related'(%)

Unrelated'(%)

HEMATOLOGICThrombocytopenia 34 15

'Anemia 21 17Neutropenia 20 10Leukopenia 10 5

BIOCHEMISTRY'Hyponatremia 13 8'Hypokalemia 2 4'Hyperglycemia 1 5CONSTITUTIONAL

'Fatigue 13 5INFECTION

'Febrile'neutropenia 5 9'Lung'infection 1 11

GASTROINTESTINAL'Dehydration 5 2'Anorexia 5 UOTHER

Muscle'weakness 3 3'Dyspnea U 5

ADVERSE'EVENTSGrade'1/2'(%)

Grade'3/4'(%)

Total'(%)

GI/CONSTITUTIONAL'Nausea 60 3 63'Fatigue 49 13 62'Anorexia 52 5 57'Vomiting 35 3 38'Diarrhea 32 3 35

'Weight'loss 25 2 27'Dysgeusia 18 P 18'Dehydration 11 5 16HEMATOLOGIC

Thrombocytopenia 7 34 41'Anemia 9 21 30

Neutropenia 5 20 25Leukopenia 3 10 13OTHER

'Hyponatremia 12 13 25'Blurred'vision 17 P 17

Muscle'weakness 8 3 12'Dizziness 12 P 12

Adverseevents,DLTsandMTD

9

CommonrelatedAEs-allgrades(≥10%ofpa2ents,n=266)

Commongrade3/4AEs(≥5%ofpa2ents,n=266)

• Mostcommonnon-hematologictoxici2eswereGIandfa2gue(Grade1/2)

• MostcommonGrade3/4toxici2eswerehematologic

•  4DLTswereobserved– Grade4thrombocytopenia(2)– MisseddosesduetoGrade2fa&gue(1)

– Withdrawal(1)

•  MTDwasnotreached

SeriousAdverseEvents

10

•  119SAEsin71of266pa2ents(27%)•  AllfatalSAEs(45)wereunrelatedtoselinexor

• Mosttotal/fatalSAEswereinAML

•  SAEsweremostfrequentwith>65mgdosingofSelinexor

•  SepsisandpneumoniamostcommonSAEs–mostlyinAML

Pa2entslostsignificantlylessweighton≤65mgselinexor

11

Number of patients per time point are indicated on the graph

0 1 2 3 4 5 6

-10

-8

-6

-4

-2

0

Time (end of cycle)

Wei

ght c

hang

e (%

bas

elin

e)

>65 mg45-65 mg4-44 mg

2134

66 1520

42

916

24

18

12

5

9

8

5

6

8

4

(p<0.001byRandomModelAnalysisofVariance)

Forpa2entson>65mgselinexor,2meonstudyand%onstudy≥4monthswasdecreasedcomparedwith

lowerdoseranges

Longer2meonstudywithdoses≤60mgvs≥65mg

12

Heme$Cancer

Evaluable$Patients

Selinexor$dose$range

Median$dose

Days$on$study$(avg$±$stdev)

%$on$study$≥4$months

40 4C44$mg 32$mg 120 31%

64 45C65$mg 60$mg 120 27%

117 >$65$mg 90$mg 90 19%

9 21C44$mg 35$mg 59 0%

17 45C65$mg 55$mg 70 24%

52 >$65$mg 90$mg 82 19%

11 5C44$mg 30$mg 140 36%

23 45C65$mg 60$mg 151 35%

31 >$65$mg 105$mg 103 13%

19 4C44$mg 37$mg 141 35%

13 45C65$mg 60$mg 113 23%

11 >65$mg 80$mg 62 18%

All$patients

AML

NHL/CLL

MM/WM

0 100 200 300 400 500 600 700 800 9000

20

40

60

80

100

Days on study (after 90 day landmark)

% o

f pat

ient

s on

stu

dy

Landmark analysis: post 90 day time on study

45-65 mg (221 d, n=22)4-44 mg (168 d, n=15)

> 65 mg (143 d, n=35)p=0.08 for 45-65 mg vs >65 mg

-100

-75

-50

-25

0

25

50

75

100

125

150

175

200400

700

1000%

cha

nge

in b

one

mar

row

bla

sts

AML

N=64

37% median baseline bone marrow blasts(range 5-96%)

-100

-75

-50

-25

0

25

50

75

100

125

150

175

200400

700

1000

% c

hang

e in

targ

et le

sion

SPD

NHL / CLL

N=45

3.3 cm2 median baseline target lesion SPD(range 0.1-18 cm2)

-100

-75

-50

-25

0

25

50

75

100

125

150

175

200400

700

1000

% c

hang

e in

M-p

rote

in o

r lig

ht c

hain

MM / WM

N=58

selinexor aloneselinexor + 20 mg dex

25 mg/dL median baseline serum M-protein(range 1.4-60 g/dL, n=28)

553 mg median baseline urine M-protein(range 380-4463 mg, n=5)

1792 mg/L median baseline dFLC(range 9.3-15128 mg/L, n=25)

Selinexordecreasedtumorburden

13

Evaluablepa&entsbasedonclinicalassessmentonlyincluded14AML,25NHL/CLLand9MM

Selinexorflatdoseresponserates

14

•  55-60mgdosingofselinexorisassociatedwithmaximalresponseHemeCancer

EvaluablePa2ents

Mediandose CR PR MR/SD PD

ORR DCR

Allmajorindica2ons

39 32mg 2(5%) 4(10%) 20(51%) 13(33%) 6(15%) 26(66%)53 60mg 5(9%) 7(13%) 25(47%) 16(30%) 12(22%) 37(69%)94 94mg 5(5%) 9(10%) 42(45%) 38(40%) 14(15%) 56(60%)

AML

9 35mg 1(11%) - 6(67%) 2(22%) 1(11%) 7(78%)

17 55mg 3(18%) - 8(47%) 6(35%) 3(18%) 11(65%)

52 90mg 4(8%) - 31(60%) 17(33%) 4(8%) 36(68%)

NHL/CLL

11 30mg 1(9%) 2(18%) 4(36%) 4(36%) 3(27%) 7(63%)

23 60mg 2(9%) 6(26%) 10(43%) 5(22%) 8(35%) 18(78%)

31 110mg 1(3%) 8(26%) 5(16%) 17(55%) 9(29%) 14(45%)

MM/WD

19 37mg - - 11(58%) 8(42%) - 11(58%)

13 60mg - 1(8%) 7(54%) 5(38%) 1(8%) 8(62%)

11 80mg - 1(9%) 6(54%) 4(36%) 1(9%) 7(63%)

MM(+20mgdex)

11 75mg 1(9%) 5(45%) 4(36%) 1(9%) 6(54%) 10(91%)

12 105mg - 2(17%) 6(50%) 4(33%) 2(17%) 8(67%)

DCR–diseasecontrolrate(SDorbe`er)

•  Selinexorhasbeenevaluatedin266pa2entswithhematologicalcancersinaPhase1trialat3-80mg/m2(4-175mg)dosed4,6,8or102mesper4-weekcycle

•  Selinexorissafeandtolerablewithbroadan2-tumorac2vityacrosshematologicalcancers

•  Pharmacokine2csforselinexorbasedonflatdosewascomparabletoBSA-baseddoseandpharmacodynamicssupportintermipentdosing

•  TheRP2Dforselinexoris60mg(flatdose)twiceweekly,baseduponop2maltherapeu2cwindowanddura2onoftreatment

SummaryandConclusions

15

Wewouldliketothank:–  Pa2entsandtheirfamilies

–  Inves2gatorsandthestudyteamsateachpar2cipa2ngcenter:

Acknowledgements

•  GabrailCancerCenter,Canton,OH

•  MDAndersonCancerCenter,Houston,TX

•  TheOhioStateUniversity,Columbus,OH

•  TomBakerCancerCentre,Calgary

•  WashingtonUniversity;StLouis,MO

•  WeillCornellUniversity;NewYork,NY

16

•  JohnTheurerCancerCentre,Hackensack,NJ

•  PrincessMargaretCancerCentre,Toronto,Canada

•  Rigshospitalet,Copenhagen,Denmark

•  Moffi`CancerCentre,Tampa,FL

•  DanaFarberCancerIns&tute,Boston,MA

•  SarahCannonResearchIns&tute,Nashville,TN

Supplementalslides

17

0 2 4 6 8 24 480

2

4

6

8

XPO

1 ex

pres

sion

in le

ukoc

ytes

(F

old

pred

ose

leve

l)

Week 1 - Dose 1

15

15

18

33 34 2018

0 2 4 6 8

Week 3 - Dose 5,6 or 7

8

7

21

10

10

0 2 4

Week 7 - Dose 17

4

4

44

4

0 40 80 120 1600

2

4

6

8

10

XPO

1 ex

pres

sion

in le

ukoc

ytes

(F

old

chan

ge o

ver b

asel

ine

4 h

afte

r dos

e)

Dose dependence of peakXPO1 mRNA induction

selinexor dose (mg) Time (hrs after dose)

XPO1 mRNA induction over time

Pharmacodynamicinduc2onofXPO1expressioninleukocytes

18

•  XPO1mRNAlevelswereinducedinleukocyteswithin4hrpostdoseandtheeffectwasnotdependentonselinexordose

•  XPO1mRNAinduc&onwassustainedforatleast48hakerthefirstdosetoalevelthatpersistedoversubsequentweeksofdosing

Number of patients per time point are indicated on the graph