1. No category

Selinexor (KPT-­‐330) Demonstrates Marked Synergy with Dexamethasone (Sel-­‐Dex) in Preclinical Models and in Pa3ents with Heavily Pretreated Refractory Mul3ple Myeloma C Chen1, M Gutierrez2, D Siegel2, J Richter2, N Wagner-Johnston3, C Hofmeister4, J Berdeja5, N
Gabrail6, R Baz7, M Mau-Sorensen8, S Trudel1, R Tiedemann1, V Kukreti1, N Areethamsirikul1,
A Azmi9, T Kashyap10, Y Landesman10, T Marshall10, J Saint-Martin10, J McCartney10, S Norori11,
M Savona10, T Rashal10, R Carlson10, M Mirza10, S Shacham10, M Kauffman10, D Reece1
(1) Princess Margaret Cancer Center, Toronto, Canada; (2) Hackensack University Medical Center,
Hackensack, NJ, USA; (3) Washington University School of Medicine, St. Louis, MO, USA; (4) The Ohio
State University, Columbus, OH, USA; (5) Sarah Cannon Research Institute, Tennessee Oncology,
Nashville, TN, USA; (6) Gabrail Cancer Center, Canton, OH, USA; (7) H. Lee Moffitt Cancer Center &
Research Institute Inc., Tampa, FL, USA; (8) Rigshospitalet, Copenhagen, Denmark; (9) Wayne State
University, Detroit, MI, USA; (10) Karyopharm Therapeutics Inc, Newton, MA, USA; (11) Ozmosis
Research Inc, Toronto, ON, Canada
TM
©2014 – Karyopharm Therapeu3cs Inc. Selinexor Mechanism of Ac3on •  Expor&n 1 (XPO1) is the major nuclear export protein for tumor suppressor proteins (TSPs) and eIF4E-­‐bound oncoprotein mRNAs (c-­‐myc, cyclins) •  SINE compounds inhibit XPO1, leading to nuclear reten&on of oncoprotein mRNAs and reac&va&on of TSPs, reducing c-­‐myc and cyclin levels and inducing selec&ve tumor cell apoptosis •  Selinexor is a novel oral SINE compound currently being evaluated in solid and hematological cancers •  Mul&ple myeloma (MM) is a ra&onale indica&on for selinexor o 
o 
o 
o 
2 ©2014 – Karyopharm Therapeu3cs Inc. XPO1 is overexpressed in MM cells and other hematological malignancies and its levels oKen correlate with poor prognosis Selinexor reac&vates p53, which is found as hemizygous dele&ons in up to 34% of MM pts, and overcomes HDM2/
MDM2 mediated p53 degrada&on Selinexor increases IκB leading to NF-­‐κB ac&va&on, commonly found in MM By trapping mRNAs bound to eIF4E, selinexor reduces expression of c-­‐myc, Cyclin D and Survivin, which are frequently overexpressed in MM Study Design •  Selinexor Phase 1/2 Study Design (NCT01607892) o 
Open label, dose escala&on study in pa&ents with advanced hematological malignancies Doses 3 mg/m2 – 80 mg/m2 10 doses/cycle (QoD 2x-­‐3x/wk) or 8 doses/cycle (QoD 2x/wk) or 4 doses/cycle (1x/wk) Modified “3+3” design o 
Safety, tolerability, efficacy, and Recommended Phase 2 Dose (RP2D) o 
o 
o 
•  Primary Endpoint •  Pa3ent Safety Criteria o  Pa&ents who have received at least one dose of selinexor •  Pa3ent Efficacy Criteria o  Pa&ents who have completed at least one cycle of dosing with selinexor Dose Escalation Cohort
Dose Expansion Cohort
MM , WM, NHL, CLL
MM : (1) 35 mg/m2, (2) 60 mg/m2
3 ©2014 – Karyopharm Therapeu3cs Inc. Pa3ent Characteris3cs -­‐ Monotherapy Characteristic
N
Patients Enrolled
35
Median Age (Range)
62 (47 – 78)
ECOG PS 0 : 1 : 2
5 : 29 : 1
Male : Female
19 Males : 16 Females
Median Prior Treatment Regiments
5 ( 2 – 13)
4 ©2014 – Karyopharm Therapeu3cs Inc. Selinexor Pharmacokine3cs in MM Pa3ents BSA-­‐Adjusted Doses A Cmax vs dose
AUC vs dose
female (10)
male (14)
1200
AUC vs flat dose
male (14)
1000
8000
Tmax = 2.6 ± 1.9 hr
(all doses)
6
600
800
AUC0-48 (h*ng/mL)
800
42
6000
t1/2 (h)
AUC0-48 (h*ng/mL)
8000
Cmax (ng/mL)
1000
Cmax (ng/mL)
Cmax vs flat dose
t1/2 vs dose
8
female (10)
10000
Flat Doses B 4
4000
600
58
75
400
400
6000
42
58
4000
75
63
63
2
2000
2000
200
male (13)
female (8)
0
0
20
40
60
Selinexor dose (mg/m2)
0
0
0
20
40
60
Selinexor dose (mg/m2)
©2014 – Karyopharm Therapeu3cs Inc. 23
23
p<0.0001 by
one-way ANOVA
p<0.0001 by
one-way ANOVA
N pts/point as listed
N pts/point as listed
0
20
40
60
Selinexor dose (mg/m2)
(A) In MM pts, Cmax and AUC are linear with BSA-­‐adjusted dose (mg/m2) up to MTD and t1/2 is independent of dose 5 200
0
0
0
20
40
60
80
100
Selinexor dose (mg)
0
20
40
60
80
100
Selinexor dose (mg)
(B) In all hematological cancer pts from Phase 1, Cmax and AUC are linear with flat dose (mg), based upon typical BSA range (1.5-­‐2.3 m2), which jus&fies transi&on to flat dosing in future trials AE incidence (% of pts)
Selinexor-­‐Related Adverse Events Occurring in ≥ 2 pts All Cycles (28 – 744 Days ) 80
≥ 35 mg/m2 Selinexor
60
N=18
Grade 1
Grade 2
Grade 3
Grade 4
40
20
0
80
≤ 30 mg/m2 Selinexor
60
N=17
40
20
N
au
Fa sea
A tigu
no e
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W m ia
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D igh i n g
eh t
y d los
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D tio
ia n
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G
lo hea
ai
pe
td
c
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tr e
Ta urb ver
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D ca e
ys rd
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Th
D us
ys ia
r
pn
Fe o m
ea
br b o
ile c y
ne t o p
u e
N tro n i a
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uk en
op ia
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ed
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Fl
as Ca sio
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at h t s
at
re
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in
ia
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i
A n
ST cr
in eas
cr e
ea d
se
d
0
– All pa&ents treated ≥ 35 mg/m2 selinexor received 8 doses/cycle – 14 of 17 pa&ents treated ≤ 30 mg/m2 selinexor received 10 doses/cycle 6 ©2014 – Karyopharm Therapeu3cs Inc. Clinical Ac3vity of Selinexor Monotherapy Best Responses in Evaluable* MM Patients – Oral Selinexor Only
(as of 1-December-2014)
Treatment
N
CBR
PR
MR
SD
PD
Selinexor Low
Dose
≤ 30 mg/m2
15
4 (27%)
--
4 (27%)
8 (53%)
3 (20%)
Selinexor High
Dose
≥ 35 mg/m2
14
3 (21%)
1 (7%)
2 (14%)
8 (57%)
3 (21%)
Total
29
7 (24%)
1 (3%)
6 (21%)
16 (55%)
6 (21%)
Responses were adjudicated according to the Interna'onal Myeloma Working Group criteria CBR=Clinical Benefit Response (PR+MR), PR=Par&al Response, MR=Minor Response, SD=Stable Disease, PD=Progressive Disease (*Six pa&ents were not evaluable for response) 7 ©2014 – Karyopharm Therapeu3cs Inc. Dexamethasone Synergis3cally Enhances Selinexor An3-­‐MM Effects Dex (nM)
Selinexor
DEX
1
10
0
0.1
100
Selinexor (nM)
!"
!"
!"
+"
P-Ser 211 GR
10
100
0
0.1
1000
Selinexor (nM)
+"
!"
+"
+"
4.5X ↑ potency
at 100 nM DEX
1
10
100
Dex (nM)
D 5
4
3
2
1
0
ve
hi
cl
e
Total GR
1
10
ex
0
0.1
100
20
l-D
10
2.3X ↑ potency
at 111 nM selinexor
40
20
Se
1
5
100 nM
ex
20
10
25 nM
60
30
D
40
15
80
B selinexor only
IC50
Se
l
60
100
GR transcriptional activation
(fold change vs vehicle)
80
20
0 nM
0.39 nM
1.6 nM
6.3 nM
Sel-Dex Combination IC50 (nM)
Cell viability (% of vehicle)
100
40
[Dex]
Dex only IC50
Sel-Dex Combination IC50 (nM)
0 nM
0.46 nM
0.15 nM
1.4 nM
4.1 nM
12 nM
37 nM
111 nM
0
0.1
C 25
[selinexor]
Cell viability (% of vehicle)
A (A) Sel-­‐Dex synergis3c cytotoxicity: MM1.S cells were incubated with selinexor or Dex alone or in combina&on for 72 hr. Resul&ng cell viability was determined using an MTT-­‐based assay (CellTiter 96®/Promega). (B) Dex sensi3vity is not essen3al for selinexor sensi3vity: Cytotoxic potency of selinexor or Dex alone or in combina&on in Dex-­‐sensi&ve (MM1.S) vs Dex-­‐resistant (MM1.R) MM cells. (C) Sel-­‐Dex synergis3c nuclear reten3on of ac3vated nuclear GR: MM1.S cells were treated with selinexor, Dex or Sel-­‐Dex, fixed and stained for P-­‐
Ser211-­‐GR* or total GR** (*4 nM selinexor ± 25 nM DEX for 24 hr; **1 μM selinexor ± 100 nM Dex for 4 hr). (D) Sel-­‐Dex synergis3c GR transcrip3onal ac3va3on: MM1.S cells were treated with 1 μM selinexor ± 100 nM DEX for 4 hr and GR binding to GR promoters was quan&fied in nuclear extracts using GR ELISA Kit /Affymetrix (p<0.001 for all pairs except Sel vs vehicle) 8 ©2014 – Karyopharm Therapeu3cs Inc. Selinexor + Dexamethasone Combina3on (Sel-­‐Dex) Study Design •  Selinexor + Dexamethasone (Dex) Study Design o 
• 
Planned approximately 20 pa&ents to be enrolled at two target dose levels: §  Group A: 45 mg/m2 selinexor + 20 mg Dex (10 pa&ents) §  Group B: 60 mg/m2 selinexor + 20 mg Dex (11 pa&ents) Dose Evalua3on o 
Determine the safety & most tolerable dose of selinexor in combina&on with Dex §  During the dose evalua&on part of the study, 60 mg/m2 was deemed intolerable (see next column AEs) Analysis below is based upon Group A pa&ents treated with selinexor 45 mg/m2 plus 20 mg Dex 9 ©2014 – Karyopharm Therapeu3cs Inc. Pa3ent Characteris3cs: Selinexor + Dexamethasone Combina3on Characteristic
N
Patients Enrolled (Group A, Group B)
10 pts 45 mg/m2, 11 pts 60 mg/m2
Median Age (Range)
63 (43 – 75)
ECOG PS 0 : 1 : 2
5 : 15 : 1
Male : Female
12 Males : 9 Females
Median Prior Treatment Regiments (Range)
8 ( 2 – 16)
10 ©2014 – Karyopharm Therapeu3cs Inc. 45 mg/m2 Selinexor + 20 mg Dex
80
N=10
60
40
Grade 1
Grade 2
Grade 3
Grade 4
20
0
Na
us
ea
Fa
tig
ue
A
no
re
xi
a
Vo
m
iti
ng
D
ia
rr
he
a
A
gi
ta
t
He ion
ad
ac
Se
he
ns
I
or nso
y
ne mn
ia
ur
op
at
hy
Dy
sp
n
D
ys ea
ge
us
Th
ia
ro
m
bo
cy
to
pe
ni
a
A
ne
m
ia
B
lu
rr
ed
vi
si
on
H
C
yp
re
on
at
in
at
in
re
e
in mia
cr
e
H
yp ase
d
ok
al
em
ia
AE incidence (% of pts)
Sel (45 mg/m2)-­‐Dex Related Adverse Events in ≥ 2 pts Group A 11 ©2014 – Karyopharm Therapeu3cs Inc. Common Related Adverse Events in ≥ 2 pts AE incidence (% of pts)
≥ 35 mg/m2 Selinexor
0
20
40
60
80
45 mg/m2 Selinexor + 20 mg Dex
0
20
40
60
80
60 mg/m2 Selinexor + 20 mg Dex
0
20
40
60
80
Nausea
Fatigue
Anorexia
Vomiting
Weight loss
N=18
N=10
N=10
Grade 1
Grade 2
Grade 3
A comparison of common AE’s for pa&ents treated on selinexor alone ≥ 35 mg/m2, Sel(45)-­‐Dex, Sel(60)-­‐Dex is shown above. Sel(45)-­‐Dex shows reduc&on in nausea grades and very liyle weight loss compared with selinexor alone. AE analysis of Group B pa&ents at 60 mg/m2 was not feasible as only 3 out of the 11 pa&ents received ≥ 7 doses of selinexor at 60 mg/m2 in Cycle 1 (1 MR, 2 SD). Although no formal DLT was observed, higher grade toxici&es were shown as compared to selinexor alone and Sel(45)-­‐Dex. The Sel(60)-­‐Dex high dose combina&on was very poorly tolerated and none of the pa&ents con&nued on twice weekly selinexor 60 mg/m2 in Cycle 2. Therefore, Sel(60)-­‐Dex represents an intolerable dose. The MTD/RP2D of Sel-­‐Dex is 45 mg/m2 + 20 mg Dex, twice weekly. 12 ©2014 – Karyopharm Therapeu3cs Inc. Time to Progression (days)
Time to Progression (TTP) on Sel-­‐Dex is Longer than Last Prior Therapy 500
400
Treatment
+
Median TTP (days)
Sel-Dex
121
Last prior therapy
92
Median Sel-Dex/Prior Therapy TTP ratio > 1.52
No. of prior therapies listed above x axis; + indicates pt still on study
300
200
+
100
0
7
5
6
9
10
9
16
3
5
76
81
99
84
92
93
98
79
90
Patient No.
All pa&ents had MM refractory to most recent therapy including Dexamethasone. Time To Progression on last therapy versus Sel(45)-­‐Dex. As of 1-­‐December-­‐2014 13 ©2014 – Karyopharm Therapeu3cs Inc. Prior Treatment Regimens – Group A Pa3ents !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Group!A!Patients!with!Rel/Ref!MM!Treated!with!Twice!Weekly
(As!of!1IDecemberI2014)!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
!!!!!!!!!!!!!!!!!!!!!Oral!Combination!–!Selinexor!45!mg/m2!+!Dexamethasone!20!mg!
!Patient! MM! Maximal!
#!Prior!
Response
ID! Type
∆
Tx
76
IgGIκ –71%
PR
7
Study!
Days
DoxIVincIDex,!TDIDex,!CarfilIDex,!VRD,!CycloIPredIBCNU,!DoxilICarfilIDex!!
301+
LenIDex,!CycloIEtopICisIMelIDexIASCT,!VRD,!CarfilICycloIDex,!CarfilICycloIDexILen,!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
15
CarmITDICisIEtopICytaIVelIMel,!CycloICarfilIPomIDex,!VorILenIDex
TDIPredIDexIASCT,!CycloIVelIDex,!LenIDex
52
Prior!Therapies
77
FLCIλ
II
NE
8
79
FLCIκ
–53%
PR
3
81
FLCIκ
–99%
sCR
5
VincIAdriaIDexIASCT,!!ASCT,!LenIDex,!CycloIPred,!PomICarfilIDex
280
84
IgGIκ
–84%
PR
9
VelIDex,!ASCT,!LenIDex,!VelIDex,!Vel,!Carfil,!PomIDex,!Carfil,!DTIPACEITD
170
90
IgGIκ
41%
PD
5
CycloIVelILenIDex!(x2),!CarfilIMelIASCT,!CycloIVelIDex,!PomICarfilIDex
31
92
IgAIκ
–55%
PR
10
VelIDex,!VRDIASCT,!Len,!Reolysin,!TG02,!CarfilIDex,!CarfilICycloIDex,!CarfilIPomIDex
121
93
IgGIκ
–41%
MR
9
98
IgGIλ
–48%
MR
16
99
IgAIκ
–82%
PR
6
VAD,!VTD+ASCT,!VelILenIDex,!Experim,!CarfilIPanob,!LenIElotuIDex,!Experim,!PomIDex,!BendaIPomIDex 114
LenIDex,!ASCT!(x2),!VelILenIDex,!VidILen,!BendaIVelIDex,!VAD,!Ritux,!VelITD,!CarfilIDex,!CarfilIDexICisI
79
Adria,!LenIRituxIInter,!CarfilIPom,!VelITDIDexIAdriaICisIATRAIArsenic!Trioxide,!LenIDex,!TG02ICarfil
Sal,!TDIDex,!Len,!ASCT,!Ibrut,!VelIDex
201+
(+)$indicates$patient$still$on$study
Prior treatment regimens for pa&ents treated with 45 mg/m2 selinexor + 20 mg Dexamethasone. Note all pa&ents received combina&ons including steroids prior to study entry 14 ©2014 – Karyopharm Therapeu3cs Inc. Time to and Dura3on of Response – Group A Pa3ents Time to and Duration of Response
81
76
Pt. No.
99
84
sCR
92
PR
MR
79
PD
93
On Study
98
WC
90
0
4
8
12
16
20
24
28
32
36
40
Weeks Following Initiation of Sel(45)-Dex Treatment
Time to response and dura&on of response as of 1-­‐December-­‐2014. Median DOR of ~7 months Pa&ents with responses (PR or MR) who withdrew consent (WC) were con&nuing to respond at WC. 15 ©2014 – Karyopharm Therapeu3cs Inc. Clinical Ac3vity Best Responses in Evaluable (N=9) Group A MM Patients
Oral Sel (45 mg/m2)-Dex (as of 1-Dec-2014)
Treatment
N
CBR
ORR
sCR
PR
MR
PD
Selinexor (45 mg/m2)
9 8 (89%) 6 (67%) 1 (11%) 5 (55%) 2 (22%) 1 (11%)
+ Low Dex (20 mg)
CBR=Clinical Benefit Response (sCR+PR+MR), ORR=Overall Response Rate (sCR+PR), sCR=Stringent Complete Response, PR=Par&al Response, MR=Minor Response, PD=Progressive Disease (*One pa&ent was not evaluable) Responses were adjudicated according to the Interna'onal Myeloma Working Group criteria 16 ©2014 – Karyopharm Therapeu3cs Inc. Clinical Ac3vity Maximal tumor volume Δ (%)
Sel (45 mg/m2)-Dex Maximal M-Protein Effect
40
20
0
-20
-40
-60
-80
-100
FLC-κ
IgG-κ
IgA-κ
IgG-κ
IgA-κ
81
84
99
76
92
Pt No.
17 ©2014 – Karyopharm Therapeu3cs Inc. FLC-κ
79
IgG-λ
IgG-κ
IgG-κ
98
93
90
MM Immunohistochemistry 040#081&(45mg/m2&+&20&mg&Dex&&/&sCR)&&
H&E$
CD138$
Bone marrow biopsies f r o m t w o m u l & p l e m y e l o m a p a & e n t s obtained pre-­‐dose and 3-­‐4 w e e k s p o s t S e l -­‐ D e x t r e a t m e n t . S t a i n i n g included CD138, NRAS (frequently mutated in MM), GR (Dex receptor) and GADD45 and MSH2 (DNA damage induced proteins). En&re sec&ons were imaged using Aperio ScanScope AT Turbo at 20x magnifica&on. Selinexor + Dex reduced CD138+ MM, induced GADD45 and MSH2, and increased nuclear GR levels. GR$
NRAS$
MSH2$
GADD45$
&040#076&(45mg/m2&+&20&mg&Dex&&/&PR)&&
Pre(Dose$
A-er$Treatment$
18 ©2014 – Karyopharm Therapeu3cs Inc. Pre(Dose$
A-er$Treatment$
Summary and Conclusions • 
XPO1 is overexpressed in MM, resul3ng in func3onal inac3va3on of TSPs and increased levels of oncoproteins such as c-­‐Myc • 
XPO1 inhibi3on by selinexor (KPT-­‐330) leads to nuclear accumula3on and ac3va3on of TSPs, as well as reduc3on in c-­‐Myc levels • 
Selinexor (oral) shows durable minor responses (MR) and disease stabiliza3on (SD) as a single agent in pa3ents with heavily pretreated MM • 
Selinexor causes nuclear reten3on and ac3va3on of the glucocor3coid receptor, with synergis3c an3-­‐MM ac3vity in combina3ons with steroids • 
Selinexor 45 mg/m2 + dexamethasone (Dex) 20 mg, both twice weekly, leads to high rates of durable responses in pa3ents with heavily pretreated refractory MM • 
This combina3on will be taken forward in addi3onal studies, including registra3on-­‐directed trials, in relapsed and/or refractory MM 19 ©2014 – Karyopharm Therapeu3cs Inc.