PX-171-004, a multicenter phase 2 study of
carfilzomib (CFZ) in patients with relapsed
myeloma: an efficacy update
R. Vij1, M. Wang2, R. Orlowski2, A. K. Stewart3, S. Jagannath4, V. Kukreti5, M. Le6,
L. Kunkel6, David Siegel7, Multiple Myeloma Research Consortium (MMRC)8
(1) Washington University School of Medicine, Saint Louis, MO, (2) Lymphoma
and Myeloma, University of Texas M.D. Anderson Cancer Center, Houston, TX, (3)
Mayo Clinic, Scottsdale, AZ, (4) St. Vincent's Comp. Cancer Ctr., New York, NY, (5)
Princess Margaret Hospital, Toronto, ON, (7) Clinical Development, Proteolix, Inc.,
South San Francisco, CA, (13) Hackensack University Medical Center,
Hackensack, NJ, (8) MMRC, Norwalk, CT
Targeting the Proteasome in Cancer
Protein degradation is critical to regulating key cell functions
Proteins are degraded by the proteasome
Proteasome inhibition causes apoptosis in cancer cells
Cancer cells are more dependent on proteasomecontrolled cell cycle
and survival pathways
The proteasome is a clinically validated target in cancer
Approved proteasome inhibitor (bortezomib) for myeloma and
lymphoma
Ub
Ub
Amino Acids
Ub
Ub
Ubiquitin (Ub)
Ub
Ub
Ub
Ub
E1, E2, E3
Ub
Ub
ATP
ATP
Protein
ADP
Antigen
Presentation
26S Proteasome
Carfilzomib:
Selective and Irreversible Proteasome Inhibitor
Carfilzomib is the first in a new class of selective and
irreversible proteasome inhibitors that are associated with
prolonged target suppression, improved antitumor activity
and low neurotoxicity
Tetrapeptide
Epoxyketone
PX-171-004 Carfilzomib Phase 2 Study Design
Population: Multiple Myeloma, relapsed after 1-3 prior therapies
CFZ administration: 20 mg/m2 IV bolus; maximum 12 cycles
Premedication: Dexamethasone 4 mg as needed
D1 D2
D8 D9
D15 D16
28day
0
cycle
Rest period
(12 days)
proteasome
inhibition
%
80
Week:
12
3
4
QDx2 weekly for 3 weeks
Primary endpoint: Overall response rate (ORR = CR + VGPR + PR)*
Secondary endpoints: DOR, PFS, TTP, OS, Safety
*IMWG response criteria
PX-171-004 Ph 2 Trial of Carfilzomib in Relapsed MM:
Baseline Characteristics
BTZ-Naïve
BTZ-Exposed
(N=14)
(N=17)
59.7
60.6
Mean Age, years
(range 38-74)
(range 47-77)
3.2
4.4
Mean Years Since Diagnosis
(range 1.3-6.4)
(range 2-13.2)
N (%)
N (%)
Gender
Male
7 (50)
8 (47)
Female
7 (50)
9 (53)
Immunoglobulin Subtype
IgG
6 (43)
14 (82)
IgA
4 (29)
1 (6)
IgD
0 (0)
1 (6)
Light Chain Only
4 (29)
1 (6)
Light Chain Subtype
Kappa
12 (86)
10 (59)
Lambda
2 (14)
7 (41)
BTZ = bortezomib
PX-171-004 Ph 2 Trial of Carfilzomib in Relapsed MM:
Baseline Characteristics
BTZ-Naïve (N=14)
BTZ-Exposed (N=17)
N (%)
N (%)
Peripheral Neuropathy
Prior History
9 (64)
14 (82)
Grade 1/2 Neuropathy at baseline
4 (29)
6 (35)
Prior Bortezomib Therapy
Single Agent
-
3 (18)
In Combination
-
14 (82)
Other Prior Therapies
Corticosteroid
16 (94)
14 (100)
Lenalidomide OR Thalidomide
13 (93)
12 (71)
Lenalidomide AND Thalidomide
3 (21)
4 (24)
Alkylator
16 (94)
13 (93)
Anthracycline
1 (7)
8 (47)
Stem Cell Transplant
15 (88)
12 (86)
BTZ = bortezomib
PX-171-004: Carfilzomib demonstrates single agent
anti-myeloma activity
100
6.5%
CR
14%
18%
VGPR
10%
PR
14%
MR
ts
SD
32%
c
14%
PD
e
47%
NE (TLS)
ubj 50
s
16%
36%
of%
ORR:
18%
26%
ORR:
57%
35.5%
14%
ORR:
6.5%
18%
3.2%
18%*
7%
0
All
Bortezomib
Bortezomib
Subjects
Exposed
Naive
(N = 31)
(N = 17)
(N = 14)
90% of responses occurred by the end of Cycle 2
*One PR is unconfirmed
PX-171-004: Responses with Carfilzomib are Durable
100
Graph represents > MR
80
freen-io 60
ess 40
ogr
pr 20
BTZ naive (N=10)
%
BTZ exposed (N=6)
0 0
100
200
300
400
Study Day
Duration of
CBR ( MR)
ORR ( PR)
Response
BTZ naïve
BTZ exposed
BTZ naïve
BTZ exposed
(months)
(N=10)
(N=6)
(N=8)
(N=3)
Median
9.7
8.4
>8.6
7.3
Range
>3.2 to >11.6
>5.8 to >10.9
>1.9 to >11.6
4.9 to >9.7
PX-171-004: Long Time To Progression
100
Intent To Treat
Population
80
-free
on 60
ressig 40
rop 20
BTZ naive (N=14)
%
BTZ exposed (N=17)
0 0
100
200
300
400
Study Day
BTZ naïve
BTZ exposed
(N=14)
(N=17)
Time to Progression (median)
11.1 months
8.3 months
Median follow up
10.8 months
12.5 months
PX-171-004: Hematologic Adverse Events
(N=31)
Overall
> Grade 3
Adverse Event*
n (%)
n (%)
Anemia
15 (48.4)
5 (16.1)
Neutropenia
13 (41.9)
3 (9.7)
Thrombocytopenia
12 (38.7)
3 (9.7)
Lymphopenia
9 (29.0)
3 (9.7)
Leukopenia
8 (25.8)
2 (6.5)
Data through April 2009
*Includes both related and non-related
PX-171-004: Most Common Non-Hematologic
Adverse Events (N=31)
Overall
> Grade 3
Adverse Event*
n (%)
n (%)
Fatigue
23 (74.2)
0
Nausea
20 (64.5)
0
Vomiting
13 (41.9)
0
ALT increased
12 (38.7)
0
URI
12 (38.7)
1 (3.2)
Dyspnea
11 (35.5)
3 (9.7)
Headache
11 (35.5)
0
AST increased
10 (32.3)
0
Diarrhea
10 (32.3)
0
Hypoesthesia
10 (32.3)
0
Hypophosphatemia
9 (29.0)
1 (3.2)
Cough
9 (29.0)
0
Pyrexia
9 (29.0)
0
Increased creatinine
8 (25.8)
1 (3.2)
Hypomagnesemia
8 (25.8)
0
Insomnia
8 (25.8)
0
Non-Neuropathic Extremity
8 (25.8)
0
Pain
*Includes AEs reported in > 25% patients
Data through April 2009
PX-171-004: Low Rate of Treatment Emergent
Peripheral Neuropathy
· 73% had a prior history of drug or disease related neuropathy
· 32% had Grade 1/2 neuropathy at baseline*
30
No study discontinuations for
peripheral neuropathy
20
(N=31)
Peripheral Neuropathy does not
limit dose or duration of therapy
bjectsus 10of% 6.5%
3.2%
0%
0
Gr1
Gr2
Gr3
(n=2)
(n=0)
(n=1)
Neuropathy AEs
*Grade Based on physical assessment at
screening (NCI-CTC scale)
Data through April 2009
PX-171-004 Conclusions: Ph 2 Relapsed MM
Single agent carfilzomib is highly active and very well tolerated in
relapsed multiple myeloma
Substantial response rate in bortezomib-naïve patients (ORR 57%)
35% of patients reached 12 cycles (~1 year) of therapy without
evidence of tumor progression or treatment-limiting adverse events
Carfilzomib achieves durable disease control with continued dosing
Median TTP of 11.1 months in bortezomib-naïve patients, 8.3 months in
bortezomib-exposed patients
Prior treatment with bortezomib does not preclude clinical benefit from
carfilzomib
AEs were generally mild and manageable
PX-171-004 Conclusions: Ph 2 Relapsed MM
Peripheral neuropathy is not a treatment-limiting toxicity with
carfilzomib
Both the rate and severity of peripheral neuropathy is significantly lower
than reported for bortezomib
Peripheral neuropathy does not appear to be a proteasome inhibitor
class effect
Dose escalation to 27 mg/m2 carfilzomib has been initiated; BTZ-
naïve cohort expanded to 115 pts
Other Carfilzomib Trials
Pivotal single arm monotherapy Phase 2 ongoing (n=250; PX-171-003)
Randomized Phase 3 lenalidomide/dexamethasone +/- carfilzomib
planned for 2010
Acknowledgements
Investigators
A. Jakubowiak, University of Michigan, Ann Arbor, MI
J. Kaufman, Emory University School of Medicine, Atlanta, GA
K. McDonagh, University of Kentucky, Lexington, KY
M. Alsina, H. Lee Moffitt Cancer Center, University of South Florida
Belch, University of Alberta Cross Cancer Center, Edmonton, AB
N. Bahlis, University of Calgary, Calgary, AB
Proteolix, Inc.
Mark Bennett, Ph.D.
Scott Cruickshank
We would like to thank all of the patients and families who
contributed to this study