Results of PX-171-003-A1, an Open-label,
Single-arm, Phase 2 Study of Carfilzomib in
Patients with Relapsed/Refractory Multiple
Myeloma
Thomas Martin, MD; David S. Siegel, MD, PhD; Michael Wang, MD; Ravi Vij, MBBS,
MD; Sagar Lonial, MD; Vishal Kukreti, MD, FRCPC; Nizar Bahlis, MD; Melissa Alsina,
MD; George Somlo, MD; Francis Buadi, MD; Frederic Reu, MD; Kevin Song, MD,
FRCPC; Lori Kunkel, MD; Alvin Wong, PharmD; Marcy Vallone; Robert Orlowski, MD,
PhD; A. Keith Stewart, MBChB; Seema Singhal, MD; Andrzej J. Jakubowiak, MD, PhD;
Sundar Jagannath; Multiple Myeloma Research Consortium (MMRC)
University of California San Francisco; John Theurer Cancer Center, Hackensack, NJ; MD Anderson Cancer Center;
Washington University School of Medicine; Emory University School of Medicine; Princess Margaret Hospital,
Toronto; University of Calgary; H. Lee Moffitt Cancer Ctr.; City of Hope, Duarte, CA; Mayo Clinic, Rochester;
Cleveland Clinic; Vancouver General Hospital; Independent Consultant; Onyx Pharmaceuticals, Inc; Mayo Clinic,
Scottsdale; Northwestern University School of Medicine; University of Michigan Comprehensive Cancer Center; Mt.
Sinai Medical Center
Rationale for Use of Carfilzomib in
Relapsed and Refractory MM
· Significant advances in MM treatment have occurred in the past
decade, including approval of several novel agents and use of highly
active combination regimens.
· The majority of patients will eventually relapse following successive
treatment regimens with progressively shorter response durations.1
· Outcomes are poor for patients who have received multiple therapies
and whose disease is relapsed and refractory following BTZ and LEN:
·
Estimated median survival of ~9 months2
·
Unmet medical need for new agents in this heavily pretreated patient population
· Carfilzomib is a novel epoxyketone proteasome inhibitor:
·
Highly selective for proteasome N-terminal threonine active sites
·
Sustained binding, potent inhibition, and minimal off-target activity
1. Richardson PG, et al. Blood. 2007; 110(10):3557-60. 2. Kumar S. et al. Haematologica. 2010;95:Abstract 0376.
1
003 Study Design
003-A01
003-A1
Study Population
(N=46)
(N=266)
Progressive disease
required at study entry
Carfilzomib
Carfilzomib
Relapsed after
20 mg/m2 IV
Dose escalation
2 prior lines of therapy
QD x 2 for 3 weeks
to 27 mg/m2
· Must include BTZ
(28-day cycle)
after 1st cycle
· Must include THAL or LEN
(maximum of 12 cycles)
Refractory to last regimen
Primary endpoint: ORR
· IMWG response criteria (IRC assessed)
Secondary endpoints
· CBR (ORR+MR), DOR, OS, PFS, TTP, safety
1. Jagannath S, et al. ASH 2009 J Clin Oncol. 2009; 27: Abstract 8504.
003-A1 Patient Disposition
003-A1 study
266 patients enrolled
Safety population
n=266
Patients excluded*
n=9
Response evaluable
n=257
*Missing baseline or post-baseline disease assessment
2
Patient Baseline Characteristics (N=266)
Median age, years (range)
63 (3787)
Median time since diagnosis, years (range)
5.4 (0.522.3)
ECOG 1, %
87
Immunoglobulin class, %
IgG
73
IgA
17
IgD
1
Cytogenetics or FISH, %
Normal/favorable
60
Unfavorable
28
Unknown or not done
12
ISS stage I / II / III, %
29 / 38 / 31
Baseline evaluation, %
Grade 1/2 neuropathy*
77
CrCl <50 ml/min
25
*Based on physical assessment at screening (NCI-CTC scale)
Prior Therapies (N=266)
Prior lines of therapy, median #
5 (range 120)
4 prior lines of therapy
82%
Prior anti-MM agents, median #
13
Progressive disease at study entry
100%
Refractory to last line of therapy
95%
PD on therapy
74%
PD within 60 days
15%
25% Response (PD at study entry)
6%
Specific prior therapies
%
Bortezomib
99.6
Immunomodulatory agent
100
Lenalidomide
94
Thalidomide
75
Corticosteroid
98
Alkylating agents
93
Stem cell transplant
74
Anthracycline
64
3
Prior Bortezomib Treatment (N=266)
Prior bortezomib, median (range)
2 (1*10)
Received bortezomib, % (n)
99.6 (265)*
Bortezomib refractory, % (n)
In line prior to study entry
44 (116)
In line any prior line
73 (193)
88%
Not refractory but intolerant to bortezomib, % (n)
15 (40)
*1 patient did not receive prior bortezomib )
Responses
(Response-evaluable Population, N=257)
DOR ( PR) and ( MR) = 8.3 mo
34.6
35
DCR = 69%
CBR = 34%
30
26.8
ORR = 24%
25
)
(%
18.7
20
15
Patients
10.1
10
5.1
5
0.4
0
CR*
VGPR
PR
MR
SD
PD
(n=1)
(n=13)
(n=48)
(n=26)
(n=89)
(n=69)
*CR IRC determined; 11 patients did not have a response that could be confirmed
4
Responses
(Higher-risk Subsets)
34
N
Yes (n=202)
P
24
en
seli
36
No (n=55)
Ba
26
32
Unfavorable (n=71)
ticse
28
engto
37
y
Normal/favorable (n=158)
C
24
t
38
50% (n=101)
emen
26
lv
vo
34
in
<50% (n=140)
M
24
B
35
ior
5 (n=147)
y
25
pr
p
ofs erath
33
<5 (n=110)
Line
25
0
5
10
15
20
25
30
35
40
CBR
ORR
Responses
(Baseline PN Population, N=202)
DOR ( PR) and ( MR) = 8.3 mo
33.2
35
DCR = 72%
CBR = 34%
30
28.2
ORR = 24%
25
)
(%
18.3
20
15
Patients
9.9
10
5.0
5
0.5
0
CR*
VGPR
PR
MR
SD
PD
(n=1)
(n=10)
(n=37)
(n=20)
(n=67)
(n=57)
*CR IRC determined; 11 patients did not have a response that could be confirmed
5
Responses
(Subsets of Interest)
45
40%
ORR
40
CBR
34%
35
31%
30%
29%
30
28%
)
24%
(% 25
tsneti
19%
19%
20
aP
17%
15
10
5
0
Yes
1 (n=122)**; DOR=8.3 mo 2 (n=135); DOR=6.9 mo
Yes
Yes
(n=227); DOR=8.3 mo
(n=116); DOR=8.4 mo
(n=184); DOR=7.8 mo
Progressive disease*
Prior BTZ lines
BTZ-refractory, last line
BTZ-refractory, any line
* On or within 60 days of last therapy; ** 1 patient did not receive prior bortezomib
Progression-free Survival
1.0
N
Median (mo)
95% CI
257
3.7
2.8 - 4.6
0.8
ts
n
n
tie
0.6
Pa
ressiog
of
tPro
0.4
uo
ith
Proportion
w
0.2
0.0
04
8
12
16
Months Since Study Entry
6
PFS by Response
Median PFS, mo
VGPR
11.6
1.0
34% of patients
PR
8.8
MR
8.1
SD
3.6
ts
n 0.8
n
PD
0.5
tie
Pa
ressiog 0.6
of
tPro
ou 0.4
ith
Proportion
w
0.2
0.0
0
4
812
16
Progression-free Survival (months)
Overall Survival
1.0
N
Median (mo)
95% CI
257
15.5 months
12.7 19.0
0.8
tsn
tie
Pa
0.6
of
iving
Surv
0.4
Proportion
0.2
0.0
0
5
10
15
20
25
Months Since Study Entry
7
OS by Response
Median OS, mo
VGPR
Not reached
1.0
PR
Not reached
MR
Not reached
ts
0.8
n
SD
12.7
tie
PD
5.3
Pa
0.6
of
iving
Surv 0.4
Proportion
0.2
0.0
0
5
10
15
20
25
Months Since Study Entry
Treatment-emergent Adverse Events* (N=266)
Any Grade, %
Grade 3/4, %
Hematologic (15%)
Anemia
44
22
Thrombocytopenia
38
27
Lymphopenia
23
18
Neutropenia
17
10
Non-hematologic (25%)
Fatigue
46
7.1
Nausea
41
1.5
Dyspnea
31
3.0
Diarrhea
29
0
Pyrexia
29
1.1
Upper respiratory tract infection
26
4.1
Headache
25
1.9
Other AEs of interest
Febrile neutropenia
0.8
0.8
Peripheral neuropathy
12
0.8
Tumor lysis syndrome
0.4
0
*Any cause
includes: neuropathy, peripheral neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy
8
Additional Safety Data (N=266)
Endpoint
%
Discontinuations
82
Due to disease progression
57
Due to AE
12
·
PN related
0
On study deaths
9.0
Due to AE
3.3
Due to disease progression
5.3
Due to AE
1.9
(considered possibly or probably related to study drug)
Patients completing 12 cycles of treatment*
16
*Patients completing the study (12 cycles, 11 months) were eligible to receive long-term extended therapy on study PX-171-010.
No evidence of cumulative toxicity in patients from 003-A1 completing >612 additional months of therapy on the extension study.
Conclusions
· Single-agent carfilzomib is active in heavily pretreated MM
patients whose disease was refractory to their last line of
therapy
· 24.1% ORR; 34.2% CBR
· Median DOR of 8.3 months (both PR and MR populations)
· Overall Survival is impressive in this patient population
· 15.5 months
· 34% of patients (MR) treated with carfilzomib had improved
PFS and OS relative to non-responders
· Carfilzomib is well-tolerated in heavily pretreated patients
· Very low rate of neuropathy -- Grade 3/4 0.8% (2 patients)
· Low rates of neutropenia
· 16% of patients completed 12 cycles
9
Acknowledgements
Thank you to all of the patients and families who contributed to this study
Additional Participating Study Investigators and Sites
· Andrew Belch, Cross Cancer Institute,
· James Mason, Scripps Clinic
University of Alberta
· Lowell Hart, Florida Cancer Specialists
· Chaim Shustik, Royal Victoria Hospital,
· Thaddeus Beeker, Southern Cancer
Montreal
Center
· David Hurd, Wake Forest University
· Laurent Gressot, Northwest Cancer
· Sarit Assouline, Jewish General
Center
Hospital, Montreal
· Jesus Berdeja, Sarah Cannon Research
· Maurizio Zangari, University of Utah
Institute
· Nashat Gabrail, Gabrail Cancer Center
All participating research nurses and data coordinators
Onyx Pharmaceuticals Inc., Emeryville, CA
Lauren Bray
Multiple Myeloma Research Consortium
Davina Moussa
Susan Kelley, MD
Emiko Miyamoto
Sandra Wear, BSN
Art DeVault, PhD
10