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
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