1. No category

A Phase 2 Study on Efficacy, Safety
and Intratumoral Pharmacokinetics
of Oral Selinexor (KPT-330) in
Patients with Recurrent
Glioblastoma (GBM)
Ulrik Lassen1, Morten Mau-Sorensen1, Andrew L Kung2, Patrick Wen3, Eudocia
Quant Lee3, Scott Plotkin4, Aida Muhic1, Tami Rashal5, Tony Williams5, Dilara
McCauley5, Joel Ellis5, Jean-Richard Saint-Martin5, Robert Carlson5, Ran
Frankel5, Sharon Shacham5, Mansoor Raza Mirza5, Michael Kauffman5,
Andrew B. Lassman2
(1) Rigshospitalet, Copenhagen, Denmark (2) Columbia University Medical Center and Herbert Irving Comprehensive Cancer
Center New York, New York (3) Dana Farber Cancer Institute, Boston, MA (4) Massachusetts General Hospital Boston, MA (5)
Karyopharm Therapeutics, Newton, Massachusetts
TM
1 ©2015 – Karyopharm Therapeu3cs Inc. XP01, Selinexor, and Glioblastoma
• 
Exportin 1 (XPO1) is a target for
glioma
•  XPO1 overexpression in glioma correlates
with higher grade and decreased overall
survival
•  XPO1 is the sole nuclear exporter of the
tumor suppressor proteins p53 and p27
which often drive glioblastoma
tumorigenesis
• 
©2015 – Karyopharm Therapeutics, Inc.
Selinexor Inhibits XPO1
• 
Selinexor (KPT-330) is a potent, covalent,
slowly-reversible, Selective Inhibitor of
Nuclear Export (SINE) that inhibits XPO1
• 
Selinexor forces nuclear retention and
activation of p53 and p27, leading to
glioblastoma apoptosis
2 In vitro and in vivo models of patient-derived GBM
A
Selinexor in vitro cytotoxic potency in
patient-derived GBM cells
Cell Line
BT 145
BT 159
BT 172
AGBM1
BT 245
DIPG 4
DIPG 6
Average
B
IC50 (µM)
0.075
0.148
0.320
0.173
0.114
0.097
0.006
0.133
(A) Selinexor cytotoxic potency in pa/ent-­‐derived GBM cells grown in neurosphere culture. Average IC50 of 133 nM is comparable to selinexor conc. in tumors of ARM A pa/ents at 2 hr (122 nM). (B)-­‐(D) Brain orthotopic GBM pa/ent-­‐derived xenograJ (PDX) model with BT-­‐145 cells treated with vehicle, selinexor (20 mg/kg 3X wkly QOD) or KPT-­‐276, a close analog of selinexor (50 mg/kg 3X wkly QOD). (B) Tumor growth over /me based on bioluminescence. AJer 61 days (the last day of vehicle arm measurement), selinexor and KPT-­‐276 induced 84% and 88% tumor growth inhibi/on, respec/vely. (C) Tumor volumes aJer 61 days with representa/ve T2 MRIs (*p<0.05; ***p>0.001). (D) Kaplan–Meier curve showing increased survival with selinexor and KPT-­‐276 of 100% and 149%, respec/vely. ©2015 – Karyopharm Therapeutics, Inc.
C
D
From Green et al . Neuro-Oncology 2014
3 KING Phase II Study Design – NCT01986348
• 
KPT-330 IN patients with recurrent Glioblastomas (KING) is an open label Phase II study in patients with recurrent
gliomas after failure of radiation and temozolomide
o  ARM A – Surgical Arm for patients who require cytoreductive surgery: ~20 patients
o  ARM B – Medical Arm for patients not eligible for surgery: ~30 patients
• 
Main Inclusion Criteria:
o  Patients ≥18 years must have received treatment with prior radiation and temozolomide
o  Measurable disease according to RANO guidelines, Karnofsky Perfomance Status ≥60
o  Prior bevacizumab was not allowed
• 
Primary Objective ARM B
o  Determine efficacy of selinexor based upon fraction of patients to achieve 6 months PFS
• 
Exploratory Objective ARM A:
o  Determine tumor concentration of selinexor and molecular effects during treatment
o  Evaluate efficacy of selinexor for patients undergoing cytoreductive surgery
• 
Treatment Scheme: ARM A & ARM B
o  ARM A – Patients received 2 doses of 50 mg/m2 selinexor QOD prior to surgery. On the day of surgery, a 3rd
dose was administered ~2 prior to surgery. Patient samples were collected for pharmacokinetic analysis predose, 1 hr and 2 hr post dose and during resection of tumor. After recovery from surgery patients resumed
selinexor dosing twice weekly for the first 3 wks of a 4 week cycle.
o  ARM B – Patients receive selinexor 50 mg/m2 twice weekly per 4 week cycle (8 doses per cycle)
©2015 – Karyopharm Therapeutics, Inc.
4 Patient Characteristics
ARM A (N=7)
Median Age (Range)
Male to Female
Median Prior Treatment Regimens (Range)
59 ( 43 – 61 )
6 Males : 1 Female
1 (1–2)
ARM B (N=17)
Median Age (Range)
Male to Female
Median Prior Treatment Regimens (Range)
©2015 – Karyopharm Therapeutics, Inc.
57 ( 43 – 61 )
12 Males : 5 Females
1 (1–2)
5 Adverse Events: ARM B
AE incidence (% of patients)
70
GR 1
GR 2
GR 3
60
50
N=17
40
30
20
10
A
no
Vo rex
D mi ia
ys tin
ge g
u
N sia
au
D se
ia a
rr
he
a
F
W a
ei t i g
Th
gh u
ro
tl e
m
os
bo
s
c
N yto
eu p
tr e n
op i a
e
L e An n i a
u k em
o p ia
H
en
yp
ia
on
at
re
B
m
lu
ia
rr
ed
v
A isio
lo
D pe n
iz c
D z i n ia
ry e
m ss
ou
th
0
ARM B: All pa/ents (N=17) were evaluable for safety. The adverse event profile is comparable to that seen in solid and hematological tumor pa/ents studied in Phase 1 trials. Approximately half of the pa/ents (N=8) required dose reduc/ons to 35 mg/m2 primarily due to fa/gue. To improve tolerability, all ongoing and newly enrolled pa/ents will move to a 60 mg (~35 mg/m2) flat dose twice weekly or 80 mg (~50 mg/m2) flat dose once weekly. ©2015 – Karyopharm Therapeutics, Inc.
6 Selinexor penetrates GBM tumors
A
[selinexor] (nM)
[selinexor] (nM)
Patient
Tumor (~2 h)
Plasma (1 h)
Plasma (2 h)
Tumor/Plasma
Patient
Tumor
(~2
h)
Plasma
(1
h)
Plasma
(2 h)0.08Tumor/Plasma
001007
142
2071
1620
142
2071
1620
0.08
001008 001007 69
1033
722
0.08
69
1033
722
0.08
001009 001008 40
311
645
0.08
40
311
645
0.08
001010 001009 291
NA
1529
0.19
291
NA
1529
0.19
001015 001010 64
986
835
0.07
64
986
835
0.07
301002 001015 211
593
562
0.37
211
593
562
0.37
301020* 301002 39
19
859
0.09
39
19
859
0.09
Average 301020*122
836
967
0.14
Average
122
836
967
0.14
*tumor specimen was collected ~6 hours after selinexor administration
*tumor specimen was collected ~6 hours after selinexor administration
A
(A) Selinexor tumor and plasma concentra/ons in GBM tumors from pa/ents in ARM A. Lower GBM tumor/plasma compared to brain/plasma ra/os in animals may be due to later Tmax in pa/ents (~4 hours). GBM tumors have comparable selinexor plasma concentra/ons at 2 hours to that of other cancer pa/ents. Average selinexor concentra/on of 122 nM in GBM tumors is equivalent to the average in vitro selinexor IC50 of 114 nM in pa/ent-­‐derived GBM cells (see bohom of first panel). B
Species
B
[selinexor] - 2 h (nM)
Brain/ Plasma
[selinexor] - 2 h (nM)
Plasma T maxBrain/
(h)
Species
Plasma
(nM) Brain (nM)
Plasma
Plasma (nM) Brain (nM)
Mouse
3970
Mouse
2920
3970
0.71
2920
0.5-1
0.71
Rat
3770
Rat
2730
3770
0.72
2730
0.5-1
0.72
Monkey
5750
Monkey
3530
5750
0.60
3530
1-3
0.60
(B) Brain availability in mice, rats and monkeys. Selinexor was also found to have brain penetra/on in animal models. Plasma and brain 0.5-1
concentra/on are shown 2 hours post 0.5-1
administra/on of 10 mg/kg selinexor. Plasma
T max (h)
1-3
©2015 – Karyopharm Therapeutics, Inc.
7 KING Patient Case Study
BASELINE
CYCLE 2
MRI brain scans of pa3ent 301-­‐005 from ARM B. 45-­‐year old male diagnosed with stage IV glioblastoma mul/form in July 2013. Selinexor was preceded by separate regimens of temozolomide, radia/on, and surgery. Selinexor monotherapy began in April 2014, leading to a par/al response in Cycle 2 with a 100% reduc/on in tumor burden (non-­‐
target lesions s/ll present). This pa/ent remained on study 175 days before progressing. ©2015 – Karyopharm Therapeutics, Inc.
8 ARM B: Efficacy and Patient Duration of Study
Days on study
A
0
30
60
90
120
150
180
210
240
!
!
!
002-018
301-005
301-013
003-023
002-017
301-001
002-014
003-019
301-022
002-021
002-011
301-003
301-004
003-024
301-012
301-006
003-016
!
!
PR
! On study
PD
! WC
PR
SD
PD
pending
PR=partial response, SD=stable disease, PD=progressive disease, WC=withdrew consent
120
B
C
100
N
PR
SD
PD
DCR
16
2 (13%)
4 (25%)
10 (62%)
6 (38%)
60
* Responses were allocated by Investigators according to Response Assessment
in Neuro-Oncology (RANO) lab based on interim unaudited data and and will be
independently verified by a central lab. DCR=disease control rate (PR+SD).
40
20
0
-20
-40
-60
301-005
301-013
301-001
002-018
002-017
003-019
003-023
301-004
002-014
301-022
-100
002-021
-80
003-016
Tumor burden (% change from baseline)
80
Best Responses* (ARM B)
S e l i n e x o r s h o w s evidence of efficacy in G B M ( a s o f 1 0 -­‐
May-­‐2015). ARM B pa/ents were evaluable f o r e ffi c a c y . ( A ) Swimmer plot depic/ng /me to response, /me on study and reasons for going off study. (B) W a t e r f a l l p l o t f o r pa/ents with quan/fied t u m o r b u r d e n . P D designa/on not shown was based on clinical symptoms. (C) Best responses and disease control rate (DCR) in ARM B pa/ents. ©2015 – Karyopharm Therapeutics, Inc.
9 Summary & Conclusions
• 
Selinexor is highly active against patient-derived GBM cells in culture, while sparing normal
neuronal and glial cells
• 
Oral selinexor is active in brain orthotopic xenografts
• 
Selinexor reaches concentrations in GBM tumors that are active in vitro against patientderived GBM cells
• 
The most common selinexor-related AEs are thrombocytopenia, fatigue, anorexia, and
hyponatremia
• 
Due to high incidence of dose reduction due to Grade 2/3 fatigue, the trial will be amended
with two arms with reduced doses
o  ARM C: 60 mg flat dose of selinexor, twice weekly
o  ARM D: 80 mg flat dose of selinexor, once weekly
• 
One patient in twelve evaluable patients on ARM B has reached 6 months PFS endpoint
• 
Selinexor shows anti-tumor activity with 13% ORR and 38% DCR in patients with pretreated
(temozolomide and radiation) GBM
©2015 – Karyopharm Therapeutics, Inc.
10