Final Results from the Bortezomibnaïve
Group of PX171004, a Phase 2 Study of
Singleagent Carfilzomib in Patients with
Relapsed and/or Refractory Multiple Myeloma
Ravi Vij,1 Jonathan L. Kaufman,2 Andrzej J. Jakubowiak,3,4 Michael Wang,5 Sundar Jagannath,6
Vishal Kukreti,7 Kevin T. McDonagh,8 Melissa Alsina,9 Nizar J. Bahlis,10 Andrew Belch,11
Frederic J. Reu,12 Nashat Y. Gabrail,13 Jeffrey Matous,14 David H. Vesole,15 Robert Z. Orlowski,16
Sandra Wear,17 Lori Kunkel,18 Alvin Wong,19 Peter Lee,20 A. Keith Stewart 21
1Washington University School of Medicine; 2Winship Cancer InstituteHematology and Medical Oncology, Emory
University School of Medicine; 3Hematology/Oncology, University of Michigan; 4Comprehensive Cancer Center
and University of Chicago; 5MD Anderson Cancer Center; 6Mount Sinai Medical Center; 7Princess Margaret
Hospital; 8University of Kentucky College of Medicine; 9H. Lee Moffitt Cancer Center; 10Tom Baker Cancer Centre,
University of Calgary; 11University of Alberta Cross Cancer Institute; 12Taussig Cancer Center Cleveland Clinic;
13Gabrail Cancer Center; 14Colorado Blood Cancer Institute; 15John Theurer Cancer Center; 16MD Anderson Cancer
Center; 17The Multiple Myeloma Research Consortium (MMRC); 18Independent Consultant, San Francisco, CA;
19Onyx Pharmaceuticals, Inc.; 20Tower Cancer Research Foundation; 21Mayo Clinic
Introduction
· Significant advances in the treatment of multiple myeloma (MM)
have occurred in the past decade, including approval of several novel
agents and use of highly active combination regimens.
· Carfilzomib is a nextgeneration proteasome inhibitor that selectively
and irreversibly binds to its target, resulting in sustained inhibition in
the absence of offtarget effects relative to bortezomib.1,2
· Carfilzomib has demonstrated durable antitumor activity and an
acceptable tolerability profile in patients with relapsed and/or
refractory (R/R) MM.3,4
· PX171004 (NCT00530816) is a multicenter, nonrandomized, open
label, singlearm phase 2 trial of singleagent carfilzomib in patients
with R/R MM who have received 13 prior lines of therapy.5
1. Demo SD, et al. Cancer Res. 2007;67:638391. 2. ArastuKapur S, et al. Clin Cancer Res. 2011;17:273443.
3. O'Connor OA, et al. Clin Cancer Res. 2009;15:708591. 4. Jain S, et al. Core Evid. 2011;6:4357.
5. Stewart AK, et al. J Clin Oncol. 2011;29:Abstract 8026.
PX171004
1
Study 004: Phase 2 Trial of Singleagent Carfilzomib
in Relapsed and/or Refractory Multiple Myeloma
Carfilzomib IV
QD x 2 for 3 weeks (28day cycle for up to 12 cycles)
BOR
BOR trea
tr t
ea e
t d*
Study Population (N=165)
Cohort 1
(n=35)
· Measurable disease
20 mg/m2
· Responsive to
BOR
BOR naïve
naïv (n=59)
1 prior therapy
· Relapsed and/or refractory
MM following 13 prior
Cohort 2
20 mg/m2 cycle 1
treatment regimens
BOR
BOR naïve
naïv (n=70)
Escalation to 27 mg/m2
· ECOG PS 02
in all subsequent cycles
Primary endpoint: ORR (CR+VGPR+PR [IMWG criteria])
Secondary endpoints: CBR (ORR+MR [EBMT criteria]), DOR, PFS, TTP, OS, safety
*Results for bortezomib (BOR)treated cohort have been reported previously (Vij R, et al. J Clin Oncol. 2010;28:Abstract 8000.
Subjects who enrolled under amended protocol allowing dose increase to 27 mg/m2 or who reconsented before
Cycle 4 start were grouped in Cohort 2.
PX171004
Patient Baseline Characteristics
Bortezomibnaïve population by cohorts (N=129)
Cohort 1
Cohort 2
Total
20 mg/m2
20/27 mg/m2
(N=129)
(n=59)
(n=70)
Median age, yrs (range)
65 (3882)
65.5 (4585)
65.5 (3885)
Median time from diagnosis, yrs (range)
3.5 (0.724.4)
3.6 (0.712.2)
3.6 (0.724.4)
Cytogenetics or FISH, n (%)
Normal/favorable
46 (78)
57 (81)
103 (80)
Unfavorable
9 (15)
10 (14)
19 (15)
ECOG performance status, n (%)
0
29 (49)
23 (33)
52 (40)
1
27 (46)
42 (60)
69 (54)
2
3(5)
5 (7)
8 (6)
International Staging System, n (%)
I
25 (42)
28 (41)
53 (41)
II
16 (27)
25 (36)
41 (32)
III
6 (10)
16 (23)
22 (17)
Baseline evaluation, n (%)
Neuropathy
29 (49)
39 (55)
67 (52)
CrCl <50 mL/min
8 (14)
12 (17)
20 (15)
PX171004
2
Prior Therapies
Bortezomibnaïve population by cohorts
Cohort 1
Cohort 2
20 mg/m2
20/27 mg/m2
Characteristic
(n=59)
(n=70)
Prior lines of therapy
Median (range)
2 (14)
2 (14)
Specific prior therapies, %
Bortezomib
0
4*
Immunomodulatory agent (Thal or Len)
93
91
Thalidomide
66
53
Lenalidomide
46
70
Corticosteroid
98
96
Alkylating agent
83
80
Anthracycline
22
24
Stem cell transplant
80
67
Refractory to most recent therapy, %
66
64
*Bortezomib exposure less than 1 cycle
PX171004
Carfilzomib Exposure and Patient Disposition
Bortezomibnaïve population by cohorts
Cohort 1
Cohort 2
20 mg/m2
20/27 mg/m2
(n=59)
(n=70)
No. Cycles started
Median (range)
7.0 (121)
6.5 (113)
Completed 12 cycles, n (%)*
17 (28.8)
29 (41.4)
Reason discontinued early, n (%)
Progressive disease
24 (40.7)
24 (34.3)
Adverse event
13 (22.0)
7 (10.0)
Other
3 (5.1)
4 (5.7)
Withdrew consent
2 (3.4)
6 (8.6)
Deaths, n (%)
Adverse event
1 (1.7)
2 (2.9)
Disease progression
0
1 (1.4)
*22 patients continued treatment beyond 1 yean on the extension protocol 010
AEs were organ failure, cardiac disorder and acute renal failure.
PX171004
3
Singleagent Antitumor Activity
Bortezomibnaïve responseevaluable population by cohorts
Cohort 1
Cohort 2
20 mg/m2
20/27 mg/m2
(n=59)
(n=67)*
Best Response, n (%)
CR
2 (3)
1 (2)
VGPR
8 (14)
18 (27)
PR
15 (25)
16 (24)
MR
10 (17)
8 (12)
SD
13 (22)
10 (15)
PD
7 (12)
11 (16)
ORR (CR+VGPR+PR)
25 (42)
35 (52)
CBR (ORR+MR)
35 (59)
43 (64)
*3 patients were not included as they did not have either baseline or postbaseline assessment.
PX171004
Consistent ORR Across Subgroups
of Clinical Interest
Category
Responses
ORR
95% CI
Overall
60
47.6
38.756.7
Dose group
20 mg/m2
25
42.4
29.655.9
20/27 mg/m2
35
52.2
39.764.6
Age (years)
<65
34
58.6
44.971.4
65
26
38.2
26.750.8
Cytogenetics or FISH
Normal/Favorable
51
51.0
40.861.1
Unfavorable
7
36.8
16.361.6
Refractory to most recent therapy
Yes
35
43.2
32.254.7
No
25
55.6
40.070.4
10
20
30
40
50
60
70
80
4
Singleagent Antitumor Activity
Bortezomibnaïve responseevaluable population by cohorts
Cohort 1
Cohort 2
20 mg/m2
20/27 mg/m2
Median, months
(n=59)
(n=67)*
Duration of response
n=25
n=35
Median, (95% CI)
13.1 (7.2NE)
NR (NENE)
Duration of clinical benefit response
n=35
n=43
Median, (95% CI)
11.5 (6.2NE)
NR (NENE)
Time to progression
n=59
n=67
Median, (95% CI)
8.3 (6.012.3)
NR (11.3NE)
Time to response
n=25
n=35
Median, (min, max)
1.0 (0.5, 3.7)
1.9 (0.5, 3.7)
Time to clinical benefit response
n=35
n=43
Median, (min, max)
0.5 (0.5, 6.5)
0.5 (0.5, 5.9)
*3 patients were not evaluable for response as they did not have either baseline or postbaseline assessment.
NE, not estimable; NR, not reached
PX171004
Progressionfree Survival
Response evaluable population
N
Median
95% CI
Cohort 1
59
8.2
(6.012.3)
20 mg/m2
1.00
Cohort 2
67
NR
(11.3NE)
n
20/27 mg/m2
oti 0.75
NE, not estimable; NR, not reached
Funcno
0.50
buti
stri
Dial 0.25
Surviv
0.00
0
5
10
15
20
25
30
Months from Start of Treatment
Number at risk:
59
33
19
7
4
67
38
33
1
0
PX171004
5
Overall Survival
Responseevaluable population
Cohort 1
Cohort 2
20 mg/m2
20/27 mg/m2
Median Followup, mo
23.2
13.8
1.00
noti 0.75
Funcno
0.50
N
Median
95% CI
buti
Cohort 1
59
NR
(NENE)
stri
20 mg/m2
Dial 0.25
Cohort 2
67
NR
(NENE)
20/27 mg/m2
Surviv
NE, not estimable; NR, not reached
0.00
0
5
10
15
20
25
30
35
Months from Start of Treatment
Number at risk:
59
51
44
40
34
13
67
60
50
20
6
0
PX171004
Adverse Events*: All Grades (20%)
Bortezomibnaïve population by cohorts
Cohort 1: 20 mg/m2 (n=59)
Cohort 2: 20/27 mg/m2 (n=70)
Treatmentemergent AEs
Any Grade, %Any Grade, %
Hematologic
Anemia
46
39
Thrombocytopenia
34
27
Neutropenia
31
30
Lymphopenia
34
19
Nonhematologic
Fatigue
71
54
Nausea
54
44
Dyspnea
49
30
Cough
39
30
Diarrhea
36
27
Pyrexia
36
33
Upper respiratory tract infection
34
29
Headache
32
33
Peripheral edema
29
26
Insomnia
19
26
Chills
25
20
Vomiting
25
20
*Shown in order of decreasing frequency as observed in the overall study population.
Regardless of relationship to carfilzomib
PX171004
6
Adverse Events*: Grade 3/4 (5%)
Bortezomibnaïve population by cohorts
Cohort 1: 20 mg/m2
Cohort 2: 20/27 mg/m2
(n=59)
(n=70)
Treatmentemergent AEs
Grade 3/4, %Grade 3/4, %
Hematologic
Lymphopenia
14
19
Anemia
12
17
Thrombocytopenia
15
11
Neutropenia
12
14
Nonhematologic
Pneumonia
14
11
Fatigue
12
1
Dyspnea
5
6
*Shown in order of decreasing frequency as observed in the overall study population.
Regardless of relationship to carfilzomib
PX171004
Treatmentemergent Events*: Neuropathy
Bortezomibnaïve population by cohorts
Number (%) of Patients
Cohort 1
Cohort 2
20 mg/m2
20/27 mg/m2
(n=59)
(n=70)
At least 1 neuropathy AE
9 (15)
13 (19)
Grade 1/2
8 (14)
13 (19)
Grade 3/4
1 (2)
0 (0)
Dose reduction
1 (2)
0 (0)
Discontinuation
0 (0)
0 (0)
*Regardless of relationship to carfilzomib
Pooled aggregate of AEs including: Peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, neuropathy
PX171004
7
SummarySingleagent Carfilzomib in
Bortezomibnaïve Patients
·
Carfilzomib showed robust and durable singleagent activity in bortezomibnaïve
patients with relapsed and often refractory MM
·
ORR of 42-52% and a CBR of 59-64% in 2 separate dose cohorts
These data are suggestive of a doseresponse relationship and are being further
evaluated in the exploratory phase 1b/2 study PX171007.
·
The most common AEs included fatigue, nausea, anemia, dyspnea, cough and
pyrexia
Majority of AEs were Grade 1/2
AEs led to discontinuation of carfilzomib in 20 (15.5%) patients (22% in Cohort 1; 10% in
Cohort 2)
·
Carfilzomib was associated with minimal peripheral neuropathy
Grade 1/2: 14% and 19%, Grade 3: 2% and 0% for Cohort 1 and 2 respectively
None lead to discontinuation of carfilzomib
·
Carfilzomib response were durable
28.8% and 41.4% of patients in Cohorts 1 and 2, respectively completed 12 cycles
Patients who were in response at the end of study were offered continued treatment
PX171004
Acknowledgments
· We would like to thank:
All of the patients who have participated in this study
All of the investigators, nursing staff, and research support staff
· Additionally we would like to acknowledge the Multiple
Myeloma Research Consortium, under whose auspices
this multisite trial is being conducted.
· Finally, we would like to thank the research teams at
Onyx Pharmaceuticals, Inc.
· This work was supported by Onyx Pharmaceuticals.
8
Additional Participating Study Investigators
and Sites
· Andrew Belch, Cross Cancer Institute,
· Nashat Gabrail, Gabrail Cancer Center
University of Alberta
· James Mason, Scripps Clinic
· Francis Buadi, Mayo Clinic, Rochester
· 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
Disclosures
Ravi Vij: Research Funding for Onyx Pharmaceuticals and Celgene; Speakers Bureau for Celgene and
Millennium; Consultancy for Onyx Pharmaceuticals. Jonathan L. Kaufman: Consultancy for Millennium, Onyx
Pharmaceuticals, Novartis, and Keryx; Research Funding for Merck and Celgene. Andrzej Jakubowiak:
Consultancy for Ortho Biotech, Celgene, Millennium, Onyx Pharmaceuticals, BristolMyers Squibb, and Exelixis;
Honoraria for Ortho Biotech, Celgene, Millennium, BristolMyers Squibb, and Exelixis; Speakers Bureau for
Ortho Biotech, Celgene, and Millennium; Board of Directors membership for Millennium, Onyx
Pharmaceuticals, and BristolMyers Squibb; Advisory committee membership for Onyx Pharmaceuticals and
BristolMyers Squibb. Michael Wang: Research Funding for Onyx Pharmaceuticals. Sundar Jagannath:
Honoraria for Millennium, Celgene, Onyx Pharmaceuticals, and Merck; Board of Directors or advisory
committee membership for Ortho Biotech, Imedex, Medicom World Wide, Optum Health Education, and PER
Group. Vishal Kukreti: Honoraria for Celgene. Kevin T. McDonagh: No relevant financial relationship(s) to
disclose. Melissa Alsina: Consultancy for Millennium and Novartis; Board of Directors or advisory committee
membership for Millennium and Novartis; Research Funding for Millennium and Allergan. Nizar Bahlis:
Honoraria and Speakers Bureau for Celgene. Andrew R Belch: Research Funding for Celgene and Onyx
Pharmaceuticals. Frederic J. Reu: No relevant financial relationship(s) to disclose. Nashat Y. Gabrail: Research
Funding for Millennium. Jeffrey Matous: Speakers Bureau for Celgene, Millennium and Cephalon. David H.
Vesole: Board of Directors or advisory committee membership for Celgene; Speakers Bureau for Celgene and
Millennium. Robert Z. Orlowski: Honoraria and Board of Directors or advisory committee membership for Onyx
Pharmaceuticals. Sandra M. Wear: No relevant financial relationship(s) to disclose. Lori Kunkel: Consultancy for
VLST Biotech, Threshold, and Onyx Pharmaceuticals. Alvin Wong: Employed by and Equity Ownership in Onyx
Pharmaceuticals. Peter Lee: No relevant financial relationship(s) to disclose. A. Keith Stewart: Consultancy and
Research Funding for Celgene, Millennium, Novartis, BristolMyers Squibb, and Onyx Pharmaceuticals.
9