PX-171-003-A0: Final Results of an
Open-Label, Single-Arm, Phase 2 Study of
Carfilzomib in Patients With Relapsed and
Refractory Multiple Myeloma
Sundar Jagannath, MD; Ravi Vij, MD; A. Keith Stewart,
MBChB; George Somlo, MD; Andrzej Jakubowiak, MD, PhD;
Suzanne Trudel, MD; Richard Schwartz, MD, Lori Kunkel, MD;
David Siegel, MD, PhD
Abstract #3541
Disclosures
In compliance with ACCME policy
Scientific Advisory Board
Millennium Pharmaceuticals
Celgene
Carfilzomib [PR-171]
Selective and Irreversible Proteasome Inhibitor
Tetrapeptide
· Peptide portion selectively binds
to substrate binding pockets
· Ketoepoxide pharmacophore
specifically reacts with catalytic
Ketoepoxide
threonine residues (5 & LMP7)
Constitutive
Proteasome
Immunoproteasome
· Irreversibly inhibits
Caspase
Trypsin-
-like
like

LMP2 MECL1
1 2
chymotrypsin-like activity




CFZ
CFZ
· Minimal inhibition of off-target




5
LMP7
proteases
Chymotrypsin-like
· At MTD >80% inhibition of
D1/D2
D8/D9
D15/D16
proteasome
0
n
Rest
0
28 Day
itio
Period
Cycle
hib
(12 days)
· Consecutive day dosing allows
proteasome
in 80
%
protracted proteasome inhibition
Week: 12
3
4
PX-171-003-A0: Phase 2 Trial of Carfilzomib in
Relapsed/Refractory Multiple Myeloma
20 mg/m2 IV push QDx2, weekly for 3 weeks
D1/D2
D8/D9
D15/D16
0
Rest Period
(12 days)
28 Day
Cycle
inhibition
proteasome
80
%
Week:
12
3
4
· Relapsed from 2 prior therapies
­ Must include bortezomib and thalidomide or lenalidomide
· Refractory to last treatment
­ 25% response on therapy
­ Progression on therapy or within 60 days of completion of therapy
· Primary endpoint: Overall response rate (CR + PR)
­
IMWG response criteria
· Secondary endpoints
­ Clinical benefit response (CR + PR + MR)
­ DOR, PFS, TTP, OS, safety
PX-171-003-A0:
Patient Characteristics (N = 46)
Patients accrued through Feb 2008
Median age, years (range)
64 (44 - 82)
Median time from diagnosis, years (range)
5.5 (1 - 15)
Gender
Male
54%
IgG
67%
IgA
20%
Immunoglobulin
subclass
IgD
2.2%
Light chain disease
10.9%
Baseline evaluation
Grade 1/2 neuropathy*
78
GFR < 60 mL/min
39
*Based on physical assessment at screening (NCI-CTC scale)
PX-171-003-A0: Prior Therapies (N = 46)
Prior Therapies, median (range)
5 (2-15)
%
4 prior therapies
80
Bortezomib
100
As last therapy
57
Immunomodulatory agent
100
Lenalidomide
89
Thalidomide
91
Corticosteroid
100
Alkylator
(Melphalan, cyclophosphamide,
94
carmustine)
Stem cell transplant
83
Anthracycline
80
PX-171-003-A0: Results (N = 39)*
50
40
41%
30
CBR=26%
ubjectsfs 20
28%
o% 10 18%
7.7%
0
PR
MR
SD
PD
(n=7)
(n=3)
(n=16)
(n=11)
CBR = 19% (5/26) in bortezomib refractory patients (2 PR, 3 MR)
* 7 subjects excluded from response analysis:
- 4 Serum free light chain only
- 2 < 1 cycle of therapy (PD)
As of April 2009
- 1 No baseline value
Carfilzomib Responses are Durable
As of April 2009
100
Months (median)
ee 80
-fr
PFS
5.1
no
PFS for PR+MR
60
7.4
(range)
(2.3 ­ 13.8)
ressi 40
g
Follow-up*
7.6
ro 20
Treatment
4.1
p
duration (range)
(1 ­ 12)
%
0 0
100
200
300
400
500
10% of pts completed 12 cycles
Time to event (days)
* Patients followed until progression or death
PX-171-003-A0 Adverse Events
003-A0 (N=46)
Adverse Event
All Grades (%)
Grade 3/4 (%)
Hematologic ( 15%)
Anemia
75
37
Thrombocytopenia
50
26
Neutropenia
22
4.3
Non-Hematologic ( 20%)
Fatigue
67
8.7
Dyspnea
28
8.7
Renal Impairment
43
15
Nausea
37
0
Constipation
13
0
Diarrhea
33
0
Hyperglycemia
26
0
Upper respiratory tract infection
37
4.3
Other
Peripheral neuropathy
17
2.2
Tumor Lysis Syndrome
4.3
4.3
* 1 fatal MSOF in A0
PX-171-003-A0 Conclusions
· Single-agent carfilzomib is active in heavily pretreated
refractory MM patients who have failed all proven
agents - 18% PR and 8% MR
· Carfilzomib is active in bortezomib refractory patients
­ PR+MR in 5/26 (19%)
· Response is durable
­ Median PFS was 5.1 months
­ Response duration was 7.4 months
· Carfilzomib is well tolerated
­ Low rate of peripheral neuropathy
­ 10% (4/39) patients completed 12 cycles
Update of PX-171-003-A1
· PX-171-003 trial amended in July 2008
­ Dose escalation to 27 mg/m2 after 1st cycle
­ Sample size increased to 250
­ Tumor Lysis prophylaxis guidelines implemented
­ Safety Oversight Group (SOG) instituted
­ Independent Review Committee for efficacy
· 140 patients enrolled to date
· SOG met in April 2009 to review the safety data of first
40 patients enrolled through November 2008
Adverse Event Comparison:
PX-171-003-A0 and PX-171-003-A1 (April 2009)
003-A0 (N=46)
003-A1 (N=40)
Adverse Event
All Grades
Grade 3/4
All Grades
Grade 3/4
(%)
(%)
(%)
(%)
Hematologic ( 15%)
Anemia
75
37
48
20
Thrombocytopenia
50
26
33
23
Neutropenia
22
4.3
15
5.0
Non-Hematologic ( 20%)
Fatigue
67
8.7
40
5.0
Dyspnea
28
8.7
33
5.0
Renal Impairment
43
15
32
2.5
Nausea
37
0
28
0
Constipation
13
0
23
0
Diarrhea
33
0
23
0
Hyperglycemia
26
0
20
0
Upper respiratory tract infection
37
4.3
18
5.0
Other
Peripheral neuropathy
17
2.2
15
0
Tumor Lysis Syndrome
4.3
4.3
0
0
* 1 fatal MSOF in A0
Summary of Carfilzomib Development in
Multiple Myeloma
· PX-171-003-A1 has been expanded (N = 250)
­ 35% dose escalation implemented (to 27mg/m2) beginning cycle 2
­ Treatment extended beyond one year
­ Pivotal trial for possible accelerated approval in this unmet need
patient population
· The toxicity profile was unchanged following dose
escalation in the first 40 patients
· Other Carfilzomib MM studies
­ PX-171-004 in relapsed MM patients bortezomib naïve
(ASCO poster #8537) - ORR 57%
­ PX-171-006 Carfilzomib in combination with Rev/Dex in relapsed myeloma
(ASCO Poster #8541) - ORR 61%
http://clinicaltrials.gov/ct2/show/NCT00511238
Acknowledgements
Participating Study Sites
· Sundar Jagannath MD, St. Vincent's Comprehensive Cancer Center
· Ravi Vij MD, Washington University School of Medicine
· David Siegel, MD, PhD, Hackensack University Medical Center
· George Somlo MD, City of Hope
· Sagar Lonial, MD, Emory Winship Cancer Institute, Emory University
· Michael Wang, MD, MD Anderson Cancer Center
· Andrzej Jakubowiak MD, PhD, University of Michigan Comprehensive Cancer Center
· Suzanne Trudel, MD, University of Toronto, Princess Margaret Hospital
· Andrew Belch MD, Cross Cancer Institute, University of Alberta
· Melissa Alsina, MD, H. Lee Moffitt Cancer and Research Institute
· Seema Singhal, MD, Comprehensive Cancer Center of Northwestern University
· Francis Buadi, MD, Mayo Clinic, Rochester
· Nizar Bahlis, MD, Tom Baker Cancer Centre, University of Calgary
· Kevin McDongah MD, University of Kentucky College of Medicine
· A. Keith Stewart MBChB, Mayo Clinic, Scottsdale
All of the participating research nurses and data coordinators
Multiple Myeloma Research Consortium (MMRC)
Proteolix, Inc., South San Francisco, CA
Susan Kelley, MD
Mark Bennett, PhD
Sandra Wear, BSN
Alvin Wong, PharmD
Thank you to all of the patients and families who contributed to this study
Cross-trial Renal Adverse Event
Summary
Renal Impairment
Dose
Trial
NAll
Gr3/4
(mg/m2)
PX-171-001
1.2-20
29
3 (10%)
0
PX-171-002
1.2-27
39
10 (26%)
1 (2.6%)
PX-171-003
20
46
20 (43%)
7 (15%)
A0
PX-171-003
20/27
40
13 (32%)
1 (2.5)
A1
PX-171-004
20
31
5 (16%)
1 (3.2%)
PX-171-007
20-36
76
12 (17%)
0
Total
261
45 (20%)
5 (2%)
PX-171-003: Acute Renal Failure
) 8
Last ARF
)
L
8
L
Dose
ARF
/d
(C3D8)
/d
g
Last
6
g
m
6
Dose
m
(
(C2D16)
e
(
4
e
in
4
in
in
in
2
End of
2
Study Visit
End of
reat
Study Visit
Creat 0
C 0
12
3
12
3 Dose
Cycle
Withheld
Cycle
MR PR
pneumonia
SD
SFLC
plasmacytoma
) 8
L
Last
8
Dose
/d
ARF
ARF
g
dL)
6
(C3D16)
m
g/ 6
Last
(
Dose
e
(m
(C2D8)
4
End of
in
4
StudyVisit
ne
in
ni
2
eat
2
ati
End of Study Visit
Cr
re
0
12
3
C 0
12
Cycle
Cycle
SD
SPEP
SD
possible TLS
Myeloma kidney
(SPEP 4.63.6 g/dL)