Phase I
l
eva uation of carfil
filzomib
(PR-171) in hematolog
)gical
malignancies
AKi
A. Keith Stewart, Owen AO
A. 'C
O'Conner, Ml
Me ilissa
Alsina, Suzanne Trudel, Andre Goy,
and Robert Z. Orlowski
ASCO Annual
Annual Meeting
June, 2007
Clinical Rationale for PR
PR-171
· P t
ro easome i h
n ibiti
hibition has been
lid
va
t
a d
e
as a therapeutic strategy
· Bortezomib therapeutic hypothesis
­ Proteasome inhibition of 65 - 80% is proven to be
effective and safe
­ Full recovery of proteasome activity may be required
between doses to reduce toxicity
toxicity
· PR-171 therapeutic hypothesis
­ It
Intensive and susti
tained proteasome ih
in ibiti
hibition can be
tolerated and will improve efficacy
2
Proteasome Inhibitor Comparison
Biochemical mechanism and selectivity
PR-171
Bortezomib
Irreversible
Slowly reversible
(keto-epoxide tetrapeptide)
(boronic acid dipeptide)
Highly
gy selective for chymotryp
ypsin-like
Inhibits both chymotryp
yypsin-like and caspase-
active site within the proteasome
like activities of the proteasome
Highly selective for proteasome
Cross reactivity with serine proteases
N-terminal threonine active sites
20S proteasome

particle
-subunit ring
IC50s (nM)
PR-171
Bortezomib

5
Chymotrypsin-
*
67

like

Caspase-like
2400
74

*
2 * 1
Trypsin-like
3600
4200
* Three distinct N-terminal
3
threonine protease active sites
PR-171 Pre-Clinical Summary
Proteasome activity recovers with t1/2~24 hr
(t
(new proteasome synth
thesis)
Cellular
One-hour treatments (mimicking in vivo exposure) are
more cytotoxic with PR 171 than with bortezomib
activities
more cytotoxic with PR-171 than with
PR-171 is cytotoxic to primary MM patient cells and
bt
bort
i
ezom b
ib
it
-resist t
an
l
ce llls lilines
Daily dosing regimens with PR-171 are well tolerated
Proteasome inhibition at MTD is greater in most tissues
In vivo
with PR-171 (>80%)
() than with bortezomib (65-75%
(
)
properties
Daily dosing schedules with PR-171 (e.g., QDx2) are
most efficacious than day 1, 4 schedule in xenograft
models
4
PR-171 (Carfilzomib) Phase 1 Studies
· Two parallel studies in hematologic malignancies
with two dose schedules
· Multiple myeloma (MM), non Hodgkin's lymphoma (NHL),
Waldenstrom's macroglobinemia (WM), Hodgkin's disease (HD)
· Relapse or refractory >2 prior treatments
· Prior bortezomib allowed, < grade 2 neuropathy allowed
· Md
Mo ifid
dified Fib
Fibonacci (3
(3 3
+ )
3) design
· Primary objectives: Safety, establish maximum
tl
tolerabl
ble dose
· Secondary obj
yjectives: Anti-tumor efficacy,
pharmacokinetics, pharmacodynamics
· Subjects treated to intolerable toxicity
toxicity or
or
progressive disease
5
Phase 1 Dose Schedules
D1
D5
D14
PX-171-001
0
· QDx5; 9 day rest
ition
· 2 week cycle
b 80
· Ct
Con i
tinuous suppression
inhi
of proteasome activity
12
meo
PX-171-002
roteas
D1 D2
D8 D9
D15 D16
D28
p
0
· QDx2
k
wee l
kly for 3
%
weeks; 12 day rest
· 4 week cycle
80
· Prevent full recovery
12
3
4
of proteasome
Time (weeks)
between doses
Effi
i
cac ous
proteasome
6
inhibition threshold
PX-171-001 (QDx5)
() Dose Escalation
September 2005-April 2007
Disease type
Responses
NHL/
MM/
Cohort
N
PR
MR
SD
HD
WD
1.2-8.4 mg/m2
15
11
4
3 NHL
11 mg/m2
3
2
1
1 MM
1 MCL*
15 mg/m2
31
2
1 WM
20 mg/m2
mg/m
5
3
2
1M
1 M
MM
Total
27
18
9
1
2
4
*Dose escalated
Objective responses in 3/5 MM/WM patients at 11 mg/m2
7
PX-171-002 (QDx2
(Q
) Dose Escalation
September 2005-April 2007
Disease type
Responses
NHL/
Cohort
N
MM/WD
PR
MR
SD
HD
4* (1 MM,
1.2-8.4 mg/m2
16
10
6
3 NHL)
11 mg/m2
4
2
2
1 MM*
15 mg/m2
mg/m
3
1
2
1M
1 M
MM*
20 mg/m2
31
2
1 MM
27 mg/m2
6
1
5
2 MM
1 MM
1 MM
Total
37
16
21
4
1
6
*Dose escalated
Objective responses in 5/9 MM patients at 15 mg/m2
8
Clinical MM Activity Summary
· Responses characterized by rapid decline in M-protein
·Responses in heavily
py pre-treated patients
­ Average of 5 prior therapies
­ Bortezomib, thalidomide/lenalidomide, transplant failures
· Duration of response 55+ - 288+ days
­ Onset of response d15 to d49
2-01-005 (15 mg/m2)
2-01-012 (MM; 27 mg/m2)
225
225
800
6
200
20
200
700
5
175
175
600
Kappa 150
150
Urinary
500
4
Serum
Light
125
125
20 mg/m2
M-Protein
M-protein
Chain
400
3
100
100 (mg
(m /2
/ 4 hr
hr) 300
(g/dL)
(mg/L)
75
75
2
50
50
200
1
25
25
100
0
0
0
0
-300 -200 -100
0
100
200
300
-900 -300
-200
-100
0
100
Study Day
Study Day
9
Rd
Responders ­ PX-171-001 (QD 5
x )
5)
Diagnosis
DOT
# prior
OR
Vel
Thal
Rev
SCT
(dose cohort)
(days)
ther.
1-04-005
MM (11 mg/m2 )
PR
78
5
+
+
-
-
1-05-003
WM (15 mg/m2)MR
75
7
-
-
-
-
1-04-008
MM (20 mg/m2)MR
45
10
++
+
+
++
· 4 SD patients (1 MM, 1 T-cell NHL, 2 MCL) with duration
on therapy 112 to 223 days
· Responding patients have been discontinued due to
"treatment fatitigue"
10
Responders ­ PX-171-002 (QDx2)
Diagnosis
TTP
# prior
OR
Vel
Thal
Rev
SCT
(dose cohort)
(days)
ther.
2-01-005
MM (15 20 mg/m2)
PR
288+
5
-
-
-
+
2-01-008
MM (20 mg/m2)
PR
233
6
+
-
-
+
2-01-009
MM (27 mg/m2)
PR
134+
6
++
+
+
-
2-01-011
MM (27 mg/m2)
MR
134
4
-
+
++
+
2-01-012
MM (27 20 mg/m2)
PR
100+
4
+
+
-
+
· 6 SD patients (2 MM, 1 T cell NHL, 2 MCL) with duration
on therapy 189+ to 413 days
11
Pharmacokinetics and
Pharmacodynamics
· Preclinical studies in rats and monkeys show that
carfilzomib is cleared from plasma within minutes
· Serum concentrations approach the limits of
detection within 1 hour
· Pharmacokinetic parameters unlikely to guide
selection of
of dose
· Pharmacodynamics of proteasome activity provides
a more biologically
biologically relevant
relevant characterization
­ Assay measures chymotrypsin-like proteasome activity
­ Whole blood and mononuclear cells examined
12
Pharmacodynamics: Proteasome
Inhibition and Clinical
Clinical Activity
Whole
W
Blood
Blood PD
PD
Assays performed
(PX-171-001 and PX-171-002)
one hour after first
dose of cycle 1
110
y l)o 100
ty ro 90
ivi ont 80
NHL/HD
70
eact ec
e
60
MM/W
MM/ M
m os 50
non-responders
ed 40
pr 30
teaso f
MM/W
MM/ M
o
20
o
Pr
responders
10
(%
(PR/MR)
0 0
1
10
30
Dose (mg/m2)
80%

proteasome inhibition
inhibition achieved at doses above 15
15 mg/m2
mg/m
13
Proteasome Recovery in PBMC ­
PX-171-002 (QDx2)
Red blood cel
PBMC
l) 120
y
dosing
it tro 100
iv n
co
2-01-007
80
acte se
2-01-008
m o 60
2-02-016
o d-e
Average
40
teas pr 20
roP of
P %
QDx
QD 2
x schedu
sch
l
edu e
(%
0
20 mg/m2
0
1
2
3
4
5
6
7
8
90
1
2
3
4
5
6
7
8
9
Day
Day
Red blood cell proteasome
PBMC proteasome activity
activity fails to recover
recovers between Day 2 and
between Day 2 and Day 8 due
Day 8 due to new
ti
to irreversibl
ible
h
mec anism
prott
teasome syn h
thesis
14
Safety and Tolerability:
Tolerability: Phase 1
· Majority of AEs are Grade
Grade 1 or
or 2
­ Gastrointestinal (nausea, vomiting, diarrhea)
­ Systemic (fatigue, pyrexia)
­ Neurologic (headache)
­ Respiratory (cough
(cough, dyspnea)
· Grade 2/3 reversible creatinine following 1st dose in
four patients heralding
pg rapid decreases in M-spike
­ 3/5 MM patients at 27 mg/m2, 1/6 MM patients at 20 mg/m2
­ Event is self-limiting if drug is held, effect does not occur on
rechallenge, subsequent treatment well tolerated
· Reversible Grade 3/4 thrombocytopenia in patients
enrolled with Grade
Grade 2 thrombocytopenia
thrombocytopenia
15
· Painful peripheral neuropathy has not been reported
DLT
DL
d
an MTD ­ PX-11
171-001 (QD )
x5
Dose level
Cycle/Day
Event
Comment
Cycle 1/
Resolved, continued on
20 mg/m2
Febrile neutropenia
Day 4
study
Cycle 1/
1/
Not resolved
resolved,
20 mg/m2
Thrombocytopenia
Day 3
discontinued (PD)
· DLTs to date are hematologic
· MTD not established
· Study continues to enroll at 15 mg/m2
16
DLT
DL and
and MTD ­ PX-171-002 (QDx2)
Dose level
Cycle/Day
Event
Comment
Cycle 1/
Resolved, continued on
27 mg/m2
mg/m
Thrombocytopenia
D8
Day 8
std
tudy
Cycle 1/
Resolved, rapid response
27 mg/m2
Hypoxia
Day 2
and continued on study
Cycle 1
Acute Renal
20 mg/m2
Recovering
/Day 2
Failure
· DLTs to date are hematologic, hypoxia and Cr
· 20 mg/m2 established as a "tolerable dose"
· 27 mg/m2 necessitates further management of first
dose effect
17
Carfilzomib Phase I Summary
· Carfilzomib is a novel irreversible inhibitor selective for the
chymotryp
yypsin-like active site of the proteasome
· Carfilzomib promotes >80% proteasome inhibition in blood
· Dose limiting toxicities
toxicities
­ Myelosuppression: cyclic reversible thrombocytopenia and
neutropenia
­ A "first dose effect" has occurred at doses >20 mg/m2 and
heralds rapid decline in M-protein
· Objective responses have been observed at doses of
carfilzomib ranging from 11 mg/m2 to 27 mg/m2
­ Ri
Rap d
id onset of response ( 1
< month)
th)
­ Responses are durable (4 to 9.5+ months)
­ Responses notedi
d in bortezomib
ib andI
d MiDf
IMiD faililures
18
­ Stable disease for >1 year
Carfilzomib Development Plan
· Carfilzomib will be further investigated in both
hematologic malignancies and solid tumors
­ Ongoing expansion to treat NHL patients
· Phase 2 studies are beginning
beginning in refractory MM
and relapsed MM patients through the Multiple
Myeloma Research
Research Consortium
· A Phase 1b study is planned for solid tumors
19
Creatinine (1st week, QDx2)
4.5
20 mg/m2
4.0
35
3.5
Dos
Do es
e
Patient #
Disease Response withheld
dL) 3.0
g/
2-01-007
MM
m 2.5
(
2-01-008
MM
PR
ne
FL
2.0
2-02-021
2-02-016
MCL
atinie 1.5
2-01-016
MM
Cr 1.0
2-01-017
MM
#3
2-06-005
MM
0.5
0.0
e
1
2
3
4
5
6
7
8
9
nli
Base
Day
3.0
27 mg/m2
25
2.5
Doses
Patient #
Disease Response withheld
dL) 2.0
g/
2-01-009
MM
PR
#2, 3, 4
m
2-01-011
MM
MR
e( 1.5
in
2-01-012
MM
PR
#3, 4
n
2-02-018
MM
eatin 1.0
2-02-017
MCL
Cr
2-06-004
MM
0.5
0.0
0.
e
1
2
3
4
5
6
7
8
9
lin
Base
Day
20
Creatinine Plots
Plots (QDx2, 27mg/m2
27mg/m )
2-01-009 (MM, 27 mg/m2) (PR)
2-01-011 (MM, 27 mg/m2) (MR)
cycle 1
cycle 2
cycle 1
cycle 2
3
Dose
2.5
Dose
)
)
L
L 2.0
/d
/d
2
(mg
(mg 1.5
ne
ne 1.0
1
reatini
reatini
C
0.5
C
0
0
00
0.0
B
0
10
20
30
40
50
B
0
10
20
30
40
50
Day
day
2-01-012 (MM,
(, 2720 mg/m2) (PR
)(
)
cycle 1 (27)
cycle 2 (20)
3
1000
)Ldg/ 2m(
ne
1
reatiniC
0
0
B
0
10
20
30
40
50
day
21