Results of an Ongoing Open-label,
Phase 2 St
St d
u y of C fil
ar zomib
ib in
Patients with Relapsed and/or
Rf
Ref
t
rac ory Multi
ltiple M l
ye oma
Ravi Vij, MD, David Siegel, MD, Jonathan Kaufman, MD,
Andrzej Jakubowiak MD, PhD, A. Keith Stewart, MD,
Sd
Sundar Jt
Jaganna h
th, MD, Vishal Kk
Kukreti
ti, MD FRCPC,
Mai Le, MD, Mark Bennett, PhD, Michael Wang, MD,
and
The Multi
ltiple Myeloma Research Consortium (MMRC)
Carfilzomib:
AN
A N
l
ove , S l
e
t
ec i
tive Pt
Proteasome Inhibit
hibitor
· Novel chemical class with
highly selective and irreversible
Te
T trapeptide
highly selective and irreversible
e
proteasome binding
Potent target inhibition
H
O
H
O
O
N
N
N
N
N
Minimal off-target activity
H
O
O
H
O
O
· Improved anti-tumor activity with
consecutive-day dosing
Epoxyketone
consecutive day dosing
In-vivo, prolonged irreversible proteosome inhibition by carfilzomib
improved anti-tumor activity.1
1
Carfilzomib has in-vitro activity in bortezomib resistant cell lines.
· No neurotoxicity in animals
No histological or
or behavioral neurotoxicity in
in animals was observed
with chronic dosing.2
1Demo S et al. Cancer Res. 2007;67:6383. 2Kirk C et al. Blood. 2008;112: 2765.
Carfilzomib Is Not Associated With
Si
ifi
gn cant Off tt
-target A t
c i
ti i
v t
ity
NonProteasomal Proteases
100
Mn 80
Vehicle
In Vitro:
100
Bortezomib
60
Bortezomib
Carfilzomib is highly
at
Carfilzomib
40
selective for the
ition
Carfilzomib
b
proteasome
20
Inhi
0
%
A
G
ase
ym
DPP2
HtrA2
easome
epsin
epsin
hC
Prot
Cath
Cath
In Vivo:
n
100
100
n
p < 0.001
io
io
Carfilzomib has
it
it
80
has
b
80
b
minimal off-target
60
60
Inhi
e Inhi
activity, inhibiting the
40
m
sin
40
proteasome but not a
ep
20
easo
th
20
0
serine protease
rot
Ca
protease
P
% -20
0
%
Collection time: 5 min postdose
Collection time: 15 min postdose
Proteasome inhibition
Cathepsin G Activity
Kapur et al. Blood. 2008;112:2657.
Carfilzomib and Bortezomib
iC
in h
Ch
i
ron c Toxicology St
Studi
dies
Chronic Toxicity Studies in Rats (6 months) and Monkeys (9 months)
Toxicity
Bortezomib (D1/D4)
Carfilzomib (D1/D2)
Tremors; reduced motor activity
Neurotoxicity
Nerve degeneration
No neurobehavioral deficits
Neurotoxicity
Nerve degeneration
Conduction velocity
No histologic changes
Decreased RBCs
Decreased platelets
Ht
Hemat l
o
i
og cal
Decreased pltlt
latelets
Decreased WBCs
No neutropenia
GI
Mucosal hyperplasia and inflammation
Cardiovascular
Sporadic cardiac inflammation
Renal
Chronic progressive nephropathy
Bross PF, et al. Clin Cancer Res. 2004;10:3954-3964.
Cavaletti G, et al. Exp Neurology. 2007;204:317-325.
Kirk CJ, et al. ASH 2008. Abstract 2765 (poster presentation).
Bortezomib Single-Agent Activity
· APEX trial in Relapsed Myeloma (1-3 prior therapies)
Md
Me i
dian
b
num er f
o prior th
th
i
erap es = 2
Types of previous therapy:
Corticosteroids
98 %
Alkylating
yg agents
g
91 %
Anthracyclines
77 %
Thalidomide
48 %
Vinca alkaloids
75 %
High-dose Therapy 67 %
Experimental or other therapy
therapy 3%
ORR = 43%
TTP = 6.2 months
Median DOR = 7.8 months
Richardson PG, et al. Blood 2007 ;10 :3557-3660.
PX-171-004 Study Design
Carfilzomib IV Bolus
QD x 2 for 3 weeks (28-day cycle)
Cohort 1
BTZ-treated
N= 155
20 mg/m2
BTZ-
BTZ naïve
Study Population
· Relapsed and/or
refractory MM following
Cohort 2
13 prior
prior treatment
2
20 mg/m cycle 1
regimens
Escalation to 27 mg/m
BTZ-naïve
2
in all subsequent cycles
Primary endpoint: Overall response rate (CR+PR) (IMWG criteria)
Secondary endpoints: Duration of response, PFS
PFS, TTP, OS, safety
*Note: Premedication with hydration and 4 mg dexamethasone in Cycle 1 only to alleviate `first dose' side effects
Key Eligibility Criteria
· Multiple myeloma with
with measurable disease
disease
Serum M-protein 1 g/dL
Urine M protein
-
200 mg/24 h
· Excluded SFLC-only and non-secretory subjects
· Relapsed or refractory disease after
after 13p
3 rior
prior
treatments
Patients had to have responded
responded to at least 1 of their
prior regimens
· ECOG 02 and creatinine clearance
clearance 30
mL/min
Baseline Patient Characteristics
Cohort 1
Cohort 2
20 mg/m2
20/27 mg/m2
BTZ-treated
BTZ-naïve
BTZ-naïve
(N=36)
(N=59)
(N=60)
Median age, years (range)
63 (4077)
64 (3882)
65 (4585)
Median yrs from diagnosis
3.6 (113)
3.5 (0.724)
3.8 (0.711)
(range)
Median serum 2 microglobulin
(range) mg/L
3.20 (1.69.8)
2.90 (1.124.5)
3.29 (1.38.1)
(range), mg/L
Immunoglobulin Subtype*, n (%)
IgG
24 (67)
33 (56)
47 (78)
IgA
5 (14)
(14)
18 (31)
12 (20)
Light Chain Only
6 (17)
8 (14)
1 (2)
Light Chain Subtype, n (%)
Kappa
24 (67)
45 (76)
42 (70)
Lambda
12 (33)
14 (24)
17 (28)
*One patient in the BTZ-treated cohort had IgD+ disease
Prior Therapies
Cohort 1
Cohort 2
20 mg/m2
20/27 mg/m2
BTZ-tt
treat d
e
BTZ
ï
-na ve
BTZ
ï
-na ve
(N=36)
(N=59)
(N=60)
Median no. of prior therapies
32
2
(range)
Prior treatments, %
Bortezomib
100
0
3
Thalidomide (Thal)
69
68
53
Lenalidomide (Len)
39
46
68
Len and Thal
31
20
32
Corticosteroid
97
98
95
Alkylating agent
89
81
83
Anthracycline
31
24
25
Stem cell transplant
81
78
68
Refractory to last therapy,* %
42
49
40
*Most patients received a combination regimen as their last therapy
Baseline Patient Characteristics
Cohort 1
Cohort 2
20 mg/m2
20/27 mg/m2
BTZ-treated
BTZ-naïve
BTZ-naïve
(N=36)
(N=59)
(N=60)
ECOG Performance Status, %
44
48
32
0
1 or 2
53
53
65
ND
3
0
2
Baseline evaluation, %
Grade 1 anemia
92
92
88
Grade 1 neutropenia
75
88
87
Grade 1 thrombocytopenia
thrombocytopenia
47
42
60
Peripheral neuropathy
50
42
43
Diabetes
25
19
15
CrCl <50 mL/min
11
14
17
Single-agent Anti-tumor Activity
BTZ-treated Cohort
Cohort 1
Response rate
20 mg/m2
(N=34)*
CR
0% ORR
VGPR
9%
21%
CBR
PR
12%
33%
MR
12%
SD
35%
PD
32%
*Response-evaluable population
Time to Progression
BTZ-treated N=34*
1.00
y
07
0. 5
75
0.50
robabilitP
0.25
TTP
0
0
3
6
9
12
15
18
Months
Median TTP, mos (95% CI)
8.1 (2.811.1)
Median DOR, mos (95% CI)
MR
8.5 (7.3NE)
PR
11.5 (7.215.2)
*Response-evaluable population;
NE=not estimable
Single-Agent Anti-tumor Activity
BTZ-naïve patients*
Cohort 1
Cohort 2
Response Rate
20 mg/m2
20/27 mg/m2
(N=53)*
(N=53)*
CR
2%
0%
VGPR
13%
ORR
CBR
17% ORR
45%
CBR
PR
30%
58%
38% 55% 62%
MR
13%
8%
SD
30%
26%
PD
9%
11%
*Response-evaluable population
Time to Progression
BTZ-naïve patients
1.00
Cohort 1
y
07
0. 5
75
Cohort 2
0.50
ProbabilitP
TT
0.25
0
0
3
6
9
12
15
18
21
24
Months
Cohort 1
Cohort 2
(N=53*)
(N=53*)
Median TTP, mos (95% CI)
8.3 (6.012.0)
11.5 (9.9NE)
Median DOR, mos(95 % CI)
MR
83
8.3 (7
(7.2NE)
11.5 (11
(11.0NE)
PR
10.2 (6.2NE)
11.5 (11.0NE)
*Response-evaluable population;
NE=not estimable
Treatment-Emergent Neuropathy Was
If
Inf
t
requen
d
an Nt
Not Treat
t
men Li
Limiti
iting
Cohort 1
Cohort 2
20 mg/m2
20/27 mg/m2
20 mg/m
20/27 mg/m
BTZ-treated
BTZ-naïve
BTZ-naïve
(N=36)
(N=59)
(N=60)
Active Grade 1/2 peripheral
50
42
43
neuropathy at baseline,* %
Treatment-emergent
neuropathy, %
16.7
11.9
15
Grade 1/2
2.8
1.7
0
Grade 3
0
0
0
Grade 4
Treatment discontinuations due
2.8%
0
0
to peripheral neuropathy, %
*Grade based on physical assessment at screening (NCI-CTC scale)
Adverse Events*
Rt
Report d
e in 20% or Gd
Grade 3 in 5% (S f
a t
e y P
l
opu ti
a
)
on
Adverse Event* (N=155)
All Grades (%)
Grade 3 (%)
Pneu
e monia
uoa
11
11
Anemia
32
9.7
Neutropenia
25
9.7
Thrombocytopenia
25
9.0
Fatigue
54
5.2
Dyspnea
34
3.9
Upper respiratory infection
28
1.9
Vomiting
25
1.9
Diarrhea
28
1.3
Headache
28
1.3
Pi
Peri h
p eral edema
21
13
1.3
Nausea
45
0.6
Pyrexia
27
0.6
Increased creatinine
creatinine
20
06
0.6
Cough
27
0
*Includes both related and non-related AEs
Incidence of On-Study Deaths* (Safety Population)
Overall, n
5
Progressive disease
2
AE related to study treatment
2
AE unrelated to study treatment
1
*Death occurring during study treatment period or within 30 days post-study treatment
Causes of deaths due to AEs
Tt
Treat
t
men
ltd
related:
lti
mu -organ fi
fa lilure (possibl
ible tumor li
lysis
d)
syndrome);
k
un nown
Unrelated to treatment: cardiac
Follow-up
· ~25% subjects remain on trial
· ~25% subjects completed
jp
the full 12 cycles
· 14 (9%) subjects continued treatment on an extension protocol
Patients (n)
Total Cycles of Carfilzomib
5< 16
1
17
218
219
121
122
2
23
Conclusions
· Single-agent carfilzomib demonstrated significant activity in
relapsed and/or refractory myeloma
In BTZ- treated patients: ORR 21%, CBR 33%
In BTZ-naïve patients:
· Cohort 1 (20 mg/m2
mg/m )
2 - ORR 45%, CBR 58%
· Cohort 2 (20/27 mg/m2) - ORR 55%, CBR 62%
Preliminary data suggest higher response rates with higher doses
· Responses and disease control are durable
Median TTP in BTZ- treated patients = 8.1 months
Median TTP in BTZ- naïve patients
· Cohort 1 = 8.3 months
· Cohort 2 = 11
11.5 months
Conclusions
· AEs were generally mild and clinically manageable
Severe peripheral neuropathy was rare and does not limit
therapy despite pre-existing symptoms
· Carfilzomib is well-tolerated for at least 12 cycles (~1 year)
Lack of significant toxicities suggests that carfilzomib is
favorable for use in combination therapies
Ti l
i
t 27
/ 2
· Trial ongoing at 27 mg/m
Acknowledgements
We would like to thank all participating co-investigators,
research nurses, study coordinators, and support staff
Participating Centers
Centers
Onyx Pharmaceuticals, Inc
Inc.
MD Anderson Cancer Center, Houston
Davina Moussa
Hackensack University Medical Center, Hackensack
Emiko Miyamoto
Winship Cancer Institute, Atlanta
Kathy Boussina
Mayo Clinic, Scottsdale
Lauren Bray
University of Michigan Hematology/Oncology
Comprehensive Cancer Center, Michigan
H. Lee Moffitt Cancer Center, Tampa
Princess Margaret Hospital, Toronto
University of Calgary
Multiple Myeloma
St. Vincent's Catholic Medical Center, New York
University of Kentucky Markey Cancer Center
Research Consortium
Cross Cancer Institute, Edmonton
Susan Kelley, MD
Royal Victoria Hospital, Montréal
Sandra Wear, BSN
Gabrail Cancer Center, Ohio
Washington University
gy School of Medicine, St. Louis
Multiple Myeloma Research Consortium
And all of the patients and families who contributed to this study.