A Phase 1b Multicenter Dose Escalation Study of
Carfilzomib plus Lenalidomide and Lowdose
Dexamethasone in Relapsed Multiple Myeloma
R. Niesvizky1, M. Wang2, W. Bensinger3, M. Alsina4, N Gabrail 5,
M. Vallone6, A.A. Gutierrez6, and M. Kauffman6
1 Weill Cornell Medical College, New York, NY; 2MD Anderson Cancer
Center, Houston, TX; 3Fred Hutchinson Cancer Research Center, Seattle,
WA; 4 H. Lee Moffitt Cancer Center & Research Center, Tampa, FL;
5Gabrail Cancer Center, Canton, OH; 6Onyx Pharmaceuticals, Inc.,
Emeryville, CA
Carfilzomib:
Selective and Irreversible Proteasome Inhibitor
Carfilzomib
Carfilz
is
the
fir
s
fir t
s in a
new
class of
selectiv
e
selectiv and
irreversible proteasome inhibitors that are associated with
prolonged target suppression, improved antitumor activity
and l ow neuroti
toxi i
c t
ity
Tetrapeptide
Ketoepoxide
PX171006
Rationale for Carfilzomib + Len/Dex (CRd)
Carfilzomib is active as a singleagent in relapsed MM
At 20 mg/m2
Bortezomib naïve: ORR 46 %,
%, TTP 7.6 months
Bortezomib pretreated: ORR 18 % TTP 5.3 months
At 27 mg/m2
Bortezomib naïve: ORR 53%
Len + Dex is a current standard of care for relapsed MM
Bortezomib + Len/Dex
(VRD)
active in relapsed
or refractory patients
but has toxicity limitations (n=62)*
BTZ 1 mg/m2 + Len 15 mg + High dose Dex
Prior therapies: 8% Len, 55% Btz, 77% Thal, 36% SCT
ORR (
PR)
69%, (MR)
84%
Carfilzomib/Len/Dex should provide superior activity to Len/Dex alone
Lack of overlapping toxicities and neuropathy should allow long term dosing
*Richardson, ASCO 2009 # 8536
PX171006
Study Objectives
Primary Objective:
To evaluate safety and determine the maximum tolerated
dose (MTD)
of
fil
car zomib
ib ith
w
l enalid
id
om e and l ow d
ose
dexamethasone in patients with relapsed MM
Secondary Objectives:
To observe early evidence of efficacy and determine PK
parameters
p
of carfilzomib
PX171006
Dose Schedule
Study Design: Phase 1b, multicenter, escalation trial
Population: Relapsed multiple myeloma: 1 to 3 prior treatments
Study Treatment :
Up to 6 dose escalation cohorts
Expansion cohort at MTD or highest protocol dose (if MTD not established)
28 day cycles
Days of Administration (dose escalation cohorts)
Agent
Cycles 1-4
Cycles 5-8
Cycles 9-16
CFZ
1, 2, 8, 9, 15, 16
1, 2, 8, 9, 15, 16
1, 2, 15, 16
Len
1-21
1-21
1-21
Dex
1, 8, 15, 22
1
1
For the E pansion
x
cohort
cohort:
Dexamethasone weekly from C1C18
CFZ on days 1,2,8,9,15,16 from C1C12
PX171006
Protocol Definitions
Eligibility
Relapsed or progressive disease after 1 3 prior therapies
Neuropathy (Grade 1/2 without pain) allowed at baseline
Platelets > 50,000/mm3; ANC > 1,000/mm3
Creatinine < 2 mg/dL or CrCl 50 mL/min
Response criteria
IMWG, EBMT, NCICTC v3.0
Dose limiting
toxicity
(DLT)
defined as:
Grade (G) >3 nonhematologic
G4 neutropenia for > 7 d and / or neutropenic fever
G4 thrombocytopenia
> 7 d
G3G4 thrombocytopenia in association with bleeding
MTD = Dose level prior to that resulting in > 2/6 DLTs
PX171006
Baseline Characteristics (N=32*)
Characteristic
Median (range
(g )
60.3
Age, years
(4381)
3.0
Time since
diagnosis,
diagnosis ye
a
ye r
a s
r
(0.35
)
21.5
n (%)
Male
15 (47)
Gender
Female
17 (53)
IgG
24 (75)
Immunoglobulin subclass
IgA
5 (16)
History
y of
Bl
Base iline ev lt
alua i
tion
24 (82)
neuropathy
*Includes all subjects enrolled in first 5 dose escalation cohorts
PX171006
Prior Therapies (N=32)
Prior Therapies
Median (range)
Number
2.5 (13)
%
Borte
Bort z
e omib
z
73
Immunomodulatory Agents
90
Lenalidomide
63
Thalidomide
43
Corticosteroid
100
Alk l
y ti
a ng At
Agents
69
Anthracycline
30
Stem Cell Transplant
80
Relapse Refractory Status
50
PX-171-006
Enrollment Overview
CFZ / LEN
Duration on
Cohort
(mg/m2
Enrolled
DLTs
Therapy
/mg)
(# of 28 day
da cycles)
cy
115 / 10
6
0
17+, 9, 4, 3, 2, 1
2
15 / 15
6
0
14+, 14+, 11, 8, 1, 1
315 / 20
8
0
11+, 11+, 10+, 10+, 10+, 8, 7, 0
420 / 20
6
0
8+, 8+, 5, 3, 2, 1
520 / 25
6
0
5+, 5+, 5+, 4+, 3, 1
62027* / 25
8
0
Expansion
2027*
27 / 25
16
*CFZ 20 mg/m2 for days 1 & 2 in first cycle; 27 mg/m2 thereafter
PX171006
Adverse Events and Toxicity (N=27*)
n (%)
All Grades
Grade 3 / 4
Adverse Events
20%
5%
Fatigue
12 (44)
No DLTs or deaths through
Cohort 5
Diarrhea
9 (33)
Neutropenia
9 (33)
6 (22)
No fatigue G3 or
Anemia
7 (26)
4 (15)
thrombotic events
Back Pain
7 (26)
()
G1 neur
opa
neur
t
opa hy
h in
2 ca
se
s s
Cough
7 (26)
with pre existing PN:
Thalidomiderelated
Dyspnea
7 (26)
Bortezomibrelated
Thrombocytopenia
6 (22)
6 (22)
Arthralgia
6 (22)
*27/32 subjects enrolled in first 5 mkb2
Rash
6 (22)
dose escalation cohorts
U Respiratory Infection
6 (22)
evaluable for safety
Hyperglycemia
5 (18)
3 (11)
Slide 10
mkb26
added footnote
mkbennett, 11/21/2009
mkb27
PX171006
Drug-related SAEs (N=32)
TO BE DISCUSSED
Cohort
SAE
Cycle Day
Treatment
2
Tra
Tr nsi
s en
e t
n , G3 sinus brady
br
c
ady ar
c dia
ar
C10 D9
Cont
Con inued
t
3G3 Upper respiratory tract infection
C7 D18
Delayed
3
Febrile neutropenia
C9 D8
Discontinued
4G3 diarrhea and G3 urinary infection
C4 D1
Discontinued
Slide 11
mkb27
Changed SAE heading, added border to first table
mkbennett, 11/21/2009
PX171006
Drug-Discontinuation* (N=32)
TO BE DISCUSSED
Cohort
Cause
Relationship
Cycle Day
1PD Renal failure
NR
C1 D23
2PD Bone disease
NR
C2 D1
3Fever Unknown Origin
NR
C1D2
3
Febrile neutropenia
Possibly
C9 D8
4G3 Pneumonia
NR
C2 D1
4
G4 Soft tissue subglott
subglot ic
t mass
NR
C1 D16
4G3 diarrhea and G3 urinary infection
Possibly
C4 D1
*7/32 subjects enrolled in first 5 dose escalation cohorts evaluable for safety
PX171006
Activity in Evaluable Patients (N = 29)
100
PR
MR
SD/PD
80
NE
sctej 60
b
fsu 40
o
CBR:
CB
%
ORR:
76%
20
55%
0
1
l
2
3
4
5
ral
(N=6) (N=6) (N=8) (N=6) (N=6)
e
*29/32 subjects enrolled in first 5
Ov
dose escalation cohorts evaluable
Cohort
for efficacy
PX171006
Activity in Evaluable Patients (N = 29)
CRd: Cohorts 15
CFZ: 15 to 20 mg/m2
LEN: 10
to
25
mg
Response
N (%)
CR/ C
n R
CR
6 (21)
VGPR
5 (17)
PR : 55%
PR
5 (17)
MR
6 (21)
MR : 76%
SD
5 (17)
SD : 93%
· All responses observed at subMTD CFZ doses
· Re
R sponses improv
impr e
ov with co
c nt
n inuing therap
ther y
ap (>3 mont
mon hs)
· Cohort 6 and expansion using CFZ 27 mg m2 / LEN 25 mg
PX171006
Response improves with prolonged
pg
treatment
tce
No Response
ubjS
MR
PR
VGPR
nCR
nC
0
5
10
15
20
Months
PX171006
Activity in Evaluable Patients (N = 29)
CRd: Cohorts 15
CFZ 1020 / LEN 1025
N (%)
Relapsed
Refractory
N= 13
N= 16
CR/nCR
4 (31)
2 (13)
VGPR
5 (38)
6 (38)
PR
6 (46)
()
10 (
63)
MR
10 (77)
12 (75)
PX171006
Duration of Response in Cohorts 15 (N=16)
()
Duration of Response
100
e
fre
80
PR
n-o 60
MR
essi
40
gror 20
P%
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Response duration (months)
· Median DOR not yet reached
PX171006
Conclusions
Carfilzomib + Len/Dex is well tolerated in subjects heavily pre
treated with BTZ and IMIDs
MTD not
hd
reached No DLTs up to cohort 6
Manageable expected hematological events
Peripheral neuropathy and DVT not observed
Prolonged administration possible (> 16 months)
Carfilzomib + Len/Dex yielded responses in the majority of subjects
ORR: 55%
(
PR); 76% (
MR)
Disease control rate = 93%
Responses improve with continuing therapy ( 3 months)
Ei
Expansion h
co ort
l
current y enrolling
2027 mg/m2 CFZ + 25 mg/day Len
Acknowledgements
The authors would like to thank all the subjects and their
families for participating in this study
Special thanks to the following people at participating sites
and at Onyx
y Pharmaceuticals:
Weill Cornell University: Megan Manco, Dorcas Eng
MD Anderson Cancer Center: Christine Samuel, Vivian Green
Fred Hutchinson Cancer Research Center: Kathy Lilleby
H. Lee Moffitt Cancer Center: Deb VanDonkelaar
Gabrail Cancer Center: Stacie Bollon, Amber Miller
Onyx Pharmaceuticals: Gerard Smits, Mark Bennett, Scott
Cruickshank
Cruick
, Kat
Ka hy
h Boussina
, Felilcia Fong, and
Tina Woo