Phase II Studies :
Novel Proteasome Inhibitors
Robert Z. Orlowski, M D
. ., Ph D
. .
Associate Professor of Lymphoma/Myeloma, and
Experimental Therapeutics
pp
, Division of Cancer
Medicine; Director, Myeloma Section
Beyond Bortezomib
· Several types
types of inhibitors could
could provide an
advantage over bortezomib
Agents with
with broader specificity that target the
ChT-L and other proteasome activities
Drugs that bind irreversibly
gy and provide a
longer-lasting inhibition of the proteasome
Compounds that specifically target proteasome
subtypes expressed in
in a tissue-type specific
fashion
Inhibitors with an improved safety profile, such
as in relation to neuropathy, and more
convenient dosing
Novel Clinically Relevant Inhibitors
Bortezomib
Epoxyketone
O
·
O
H
N
OH
N
B
inhibitor carfilzomib
H
O
OH
· Lactacystin
Carfilzomib
analogue
O
O
H
H
N
N
salinosporamide A /
O
N
salinosporamide A
N
N
H
H
O
O
O
NPI-0052
O
· Other inhibitors
NPI-0052
O
CEP-18770
O
H
O
H
CH3
· Pt
Pep id
tid l
y bt
-boronate
HN
Orlowski, RZ & Kuhn, DK. Clin.
Cl
H
H
Cancer Res 14:1649, 2008.
O
NPI-0052
· Inhibits the ChT-L
activity with a Ki
comparable to that of
bortezomib
0.3 nM vs. 0.5 nM
· More potent at inhibiting
the trypsin-like activity
· Predominantly activates
apoptosis through
induction of caspase-8
with little caspase-9
Chauhan, D et al. Cancer Cell 8:407, 2005.
Novel Properties
Properties
· NPI may
may be a more
more
potent inhibitor of NF-B
signaling
gg
RR
R
R
· Irreversible inhibitor is
able to overcome
SS S
bortezomib resistance in
some primary clinical
sampld
les, and showed
enhanced activity
Chauhan, D et al. Cancer Cell 8:407,
2005.
PR-
PR 171 / Carfilzomib
Carfilzomib
· Carfilzomib activates
Carfilzomib Bortezomib
the pro-apoptotic c-
Veh
24
48
24
48
h
JNK pathway more
-p-JNK
strongly than
-tt
total JNK
strongly than
JNK
bortezomib
-Actin
· Also induces dual
capsase-8 and -9
. 8
Carfilzomib
tion
6
Bortezomib
activation, but more
nducIe 4
pas
pott
ten l
s
tly
a 2
Cld
0
Possibly due to
Fo
Caspase-3
Caspase-8
Caspase-9
irreversible binding
Kuhn, DJ et al. Blood 110:3281, 2007.
Notable
80
n
70
Properties
)ib 60
eratio
m
if
50
· Overcomes
ol
ezo
pr
rto 40
of
B 30
on
bt
bortezomib
ib
etov 20
nhibiti
10
I
(relati
resistance in
%
0
10
-
MM-6
MM-13 MM-14 MM-15
MM-17 MM-20
MM-23
many primary
Combination Indices
clinical samples
Dexame
Dexam thasone (M)
· Strong
15 10
15
10
)M 1 0.1 0.2 0.1 0.1 0.3 0.6
n
synergistic
(b 2.5 0.3 0.3 0.3 0.2 0.3 0.7
mio 5 0.5 0.5 0.5 0.9 0.5 0.6
activity with
5
05 05 05
09 05 06
activity
ilz
10 0.8 0.9 0.9
0.1 0.2 0.5
Carf
dexamethasone
RPMI 8226
KAS-6/1
and other agents
g
Kuhn, DJ et al. Blood 110:3281, 2007.
Phase I Trials of PR-
PR 171
D1
D4
D8
D11
Bortezomib dose and schedule
0
· BIW (D1/D4) x 2; 10 day rest
· 3 week
week cycle
· Maximum proteasome inhibition
of 70% in blood with full
80
recovery of the proteasome
ibition
between doses
D1
D5
inh
0
PR-171 Schedule 1
ome
· QD x 5; 9 day rest
s
· 2 week
week cycle
80
· Continuous suppression of
proteasome activity
protea
D1 D2
D8 D9
D15 D16
%
0
PR-171 Schedule 2
0
· QD x 2 weekly for 3
weeks; 12 day rest
· 4 week cycle
80
time
· Prevent full
full recovery
recovery of
of
proteasome between
12
34
Efficacious
Time (weeks)
doses
proteasome
inhibition threshold
2009 IMW Abstract
Abstract 5718
PX-171-003 : Preliminary Results of an
Open-Label, Single-Arm, Phase II Study of
Carfilzomib in Patients With Relapsed and
Refractory Multiple Myeloma
Sundar Jagannath, MD
MD, Ravi
Ravi Vij
Vij, MD, A. Keith
Keith Stewart,
MBChB, George Somlo, MD, Andrzej Jakubowiak, MD, PhD,
Tony Reiman, MD, Suzanne Trudel, MD, Jessica Taylor, BA,
Diana F h
u rman, BSN, S
t
co t
tt C i
ru k
c
h
s
k
an , MS, Ri h
c
d
ar
Schwartz, MD, Lori Kunkel, MD, David Siegel, MD, PhD and
The Multiple My
pyeloma Research Consortium
Design
· Enrolled patients with
with relapsed
relapsed & refractory
refractory
myeloma after at least 2 prior lines of
therapy
Must have included bortezomib
Must have included thalidomide and/or
lenalidomide
· Carfilzomib 20 mg/m2 iv on days 1, 2, 8, 9,
15, and 16 of every 28-day cycle
Dex 4 mg given prior to each dose in cycle 1
only
· Primary endpoint: ORR (CR + VGPR + PR)
Hematologic Adverse
Adverse Events
QuickTimeTM and a
decompressor
are needed to see this picture.
·Cyclic thrombocy
yytopenia
p
as seen with
bortezomib
Non-Hematologic AEs (N = 46)
QuickTimeTM and a
decompressor
are needed to see this picture.
Creatinine Changes
· In most patients who
who developed
creatinine changes, these were
transient, reversible, and not cumulative
· Four patients did develop acute renal
fi
fa lilure, f
o whi
hich two
d
reverse
One with myeloma kidney, another tumor
li
lysis
In two others, this was associated with
clinical deterioration
Efficacy : Response
Response Rate
Rate
50
· 26% PR+MR rate
40
ts
out of 39 patients
c
41%
je 30
CBR=26%
95% CI 13-42%
b
*
u
7 excluded
20
28%
fso
· 5f
5 free lili h
g t
ht ch i
a n
% 10
only or no baseline
13%
13%
· 2 had <1 cycle
0
PR
MR
SD
PD
· 6/10 responses
(n=5)
(n=5)
(n=16)
(n=11)
seen in cycle 1
Extended Treatment Duration
· Extended treatment durations
QuickTimeTM and a
decompressor
due to excellent tolerability
are needed to see this picture.
· Activity in face of resistance to
bortezomib-based
combinations
QuickTimeTM and a
decompressor
are needed to see this picture.
2009 IMW Abstract
Abstract 6116
61
Initial Results of PX-171-004, an Open-Label,
Single-Arm, Phase II Study of Carfilzomib
(CFZ) in Patients With Relapsed Myeloma
(MM)
Ravi Vij, MD
MD, Michael
Michael Wang
Wang, MD, Robert Orlowski
Orlowski, MD, PhD,
A. Keith Stewart, MBChB, Sundar Jagannath, MD, Vishal
Kukreti, MD, FRCPC, Jessica Taylor, BA, Diana Fuhrman,
BSN, Scott Cruickshank, MS, Richard Schwartz, MD, Lori
Kunkel, MD, David Siegel, MD, PhD and The Multiple
Myeloma Research
Research Consortium (MMRC)
Design
· Enrolled patients with
with relapsed
relapsed myeloma
who had 1-3 prior lines of therapy
Bortezomib-naïve
Bortezomib responsive (>6 mos.)
Bortezomib non-responsive (<6
(6 mos.
mos. duration)
· Carfilzomib 20 mg/m2 iv on days 1, 2, 8, 9,
15, an
a d 16 of
o ev
e ery 28-day cycle
Dex 4 mg given prior to each dose in cycle 1
only
· Primary endpoint: ORR (CR + VGPR + PR)
Non-Hematologic AEs
QuickTimeTM and a
decompressor
are needed to see this picture.
Response Summary
Summary
100
6.5
CR
10.0
18.0
10
14.0
VGPR
PR
MR
29.0
SD
%)
45.0
PD
(
50
59.0
NE (TLS)
Pts
3.0
36.0
ORR:
26.0
ORR:
60
6.0
57.0%
ORR:
35.5%
14.0
6.5
18.0
18.0%
7.0
0
3.0
All Pts
Bort
Bort
(N = 31)
Ed
Exposed
Ni
Naive
(N = 17)
(N = 14)
· 90% of responses seen by the end of
cycle 2
Treatment Duration
QuickTimeTM and a
decompressor
are needed to see this picture.
*
*
12
n
* *
* *
* on study
* *
o
* *
*
10
ti
*
CR
VGPR
ra
PR
u
) 8
s
MR
le
SD
tdn c
n
6
PD
e
y
m
(c 4
reat
2
T
Estimates of TTP
QuickTimeTM and a
decompressor
are needed to see this picture.
Adverse Events
Events of Interest
50
40
· Low rate of peripheral
tsc 30
neuropathy; none of
jeb
suf 20
o
grade 3 or
or 4
%
10
3.3%
· Two episodes of tumor
0%
0%
0
Gr1
Gr2
Gr3
li
lysis in b t
or ezomib
ib-
(n=1)
(n=0)
(n=0)
Peripheral Neuropathy AEs
naïve patients seen
· Since prophylaxis was
instituted, no recurrent
episodes in >80 patients
Conclusions
· Irreversible proteasome inhibitors like
carfilzomib and NPI-0052 may offer
advantages compared to bortezomib
· Phase II studies of carfilzomib show
t l
o
bilit
era
y
d
an d
bl
ura e ffi
e cacy,
possibly supporting accelerated
l
approva in
ti
pa
t
en s
i
w th
ith
relapsed/refractory disease
Conclusions II
· Favorable toxicity profile supports their
use in the front-line setting, and in
combinations with other active anti-
myeloma agents
· Mb
May be more
i
su t
it d
e for l
t
ong- erm
therapy, such as in a maintenance
tti
se ng, or in
t
pa i
ti
t
en s
ith
w
t
asymp
ti
oma c
myeloma or high-risk MGUS
Future Directions
· Orally available proteasome inhibitors
Greater convenience
· Immunoproteasome i hibit
n
ors
Greater specificity
20S
20Si
2
2i
RN3
RN3
1
1
5i
5
Kuhn, DJ et al. Blood
Blood preprint online,
1i
Dec. 2, 2008.
M IPSI-001