Carfilzomib and other New
Proteasome Inhibitors: Clinical Data
Andrzej J. Jakubowiak, David S. Siegel,
Ravi Vij, Sundar Jagannath, Ruben
Niesvizky, Paul G. Richardson
2
Disclosures
Consultant without honoraria for Millennium, Onyx, and
BristolMyersSquibb
1
3
Background
Since the introduction of bortezomib, proteasome inhibition
has been validated as a highly effective strategy in the
treatment of multiple myeloma.
The development of peripheral neuropathy and other
toxicities can limit extended use of bortezomib at full dose
and thus curtail its potential effectiveness.
Moreover, resistance to bortezomibbased therapy can
emerge over time.
A second generation of proteasome inhibitors, have entered
clinical trials with the intent of
· Reducing side effects
· Overcoming resistance
· Improving efficacy
· More convenient drug delivery
4
Carfilzomib (PR171): Unique Features
Tetrapeptide
Epoxyketone
O
O
New chemical class
H
H
N
N
O
N
N
N
H
O
O
H
O
O
Selective inhibitor of
chemotryptic site
In Vitro
In Vivo
(HT -29 tumor cell line)
(rat/mouse adrenal)
Irreversible more
ity
100
100
iv
l)
BTZ
ct
o 80
80
(D1/D4)
sustained target inhibition
Ae
60
ontr
BTZ
60
m
c 40
40
of
CFZ
CFZ
20
teaso
(%
20
(D1/D2)
ro
0
P
0
0
4
8
12
0
24
48
72
Time (hr)
Time (hr)
Overcomes bortezomib resistance in preclinical models
Adapted from Kuhn DJ, et al. Blood. 2007; Demo SD Cancer Res. 2007; Kirk, CJ ASH 2008; Arastu-Kapur ASH 2008
2
5
Carfilzomib Phase II 003 Study:
Study Design and Efficacy
Study Population
Median years since dx
5.4
Study expanded
003A1 (N=266)
Progressive disease required at study entry
Median lines of therapy
5
to pivotal trial
Carfilzomib
Relapsed from
Dose escalation
PD at study entry, %
100
2 prior lines of therapy
to 27 mg/m2
· Must include BTZ
Prior bortezomib, %
99.6
after 1st cycle
· Must include THAL or LEN
(maximum 12 cycles)
Refractory to Btz, %
73
Refractory to last regimen
Intolerant to Btz, %
15
DOR ( PR) and ( MR) = 8.3 mo
34.6%
35
DCR = 69%
30
CBR = 34%
26.8%
Patients
25
ORR = 24%
003A0 (N=46)
18.7%
of
20
Carfilzomib
15
20 mg/m2 IV
10.1%
QD x 2 for 3 weeks
10
(28day cycle)
5.1%
5
Percentage
0.4%
0
CR*
VGPR
PR
MR
SD
PD
(n=1)
(n=13)
(n=48)
(n=26)
(n=89)
(n=69)
Siegel DS, et al. Blood (ASH Annual Meeting Abstracts).
* CR IRC determined; 11 patients did not have a response that
2010;116:Abstract 985 (oral presentation).
could be confirmed
6
Carfilzomib 003A1:
Additional Study Highlights
Bortezomibrefractory patients
· Response rates comparable to overall population
Welltolerated
· Low rate of neutropenia
· Very limited peripheral neuropathy
· No emergence of cumulative toxicity after extended treatment
Martin T, et al. IMW 2011: Abstract O13
3
7
Carfilzomib 003A1 Study:
Impact of Cytogenetics
DOR
Normal/favorable
Unfavorable
(N=158)
(N=71)
Median mo
Efficacy
8 (610)
7 (410)
(95% CI)
Normal/favorable
Unfavorable*
(N=158)
(N=71)
Overall response rate
24.1 (17.631.5)
28.2 (18.140.1)
(>PR) % (95% CI)
Clinical benefit rate
37.3 (29.845.4)
32.4 (21.844.5)
(>MR) % (95% CI)
*Hypodiploidy or chromosome 13 deletion by metaphase,
and/or del 17p13, t(4:14), or t(14;16) by FISH
Es mate using the KaplanMeier method
Jakubowiak AJ, et al. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 1942.
8
Carfilzomib Phase II 004 Study
Study Design
Clinical Data
Study Population
Relapsed or refractory after 13
Cohort 1
Cohort 2
prior lines of therapy
20 mg/m2
20/27 mg/m2
· At least MR to first line
(N=59)
(N=64)
· Included Btz naïve pts
Best response, n (%)
ORR (CR + VGPR + PR)
25 (42)
34 (53)
CBR (ORR + MR)
35 (59)
40 (63)
TTP, mo (95% CI)
8.3 (6.012.3)
NR (10.2NR)
Cohort #1 (N=59)
Cohort #2 (N=66)
Carfilzomib
Carfilzomib
20 mg/m2 IV
Dose escalation
· Response rate in bortezomib naïve patients was 54%
QD x 2 for 3 weeks
to 27 mg/m2
· Comparable toxicity profile to 003 study
(28day cycle)
after 1st cycle
· Only very limited peripheral neuropathy
(maximum 12 cycles)
· Median lines of prior therapy: 2 (range 14)
· Refractory to most recent regimen 44 (35%)
Vij R, et al. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 1938.
4
9
Carfilzomib in Newly Diagnosed Myeloma:
CRd Frontline Study
Rationale
·
Combining Cfz with other antimyeloma drugs and moving to newly diagnosed myeloma was
a next logical step
·
The combination of Cfz + Len + Dex (CRd) has shown synergy in preclinical studies and
promising activity and tolerability in relapsed/refractory MM1,2
Frontline CRd Study Schema
Eligibility: Newly diagnosed MM requiring first line therapy (transplant eligible and ineligible)
Initial Treatment: Eight 28day cycles
1
8
15
22
28
Cfz Cfz
Cfz Cfz
Cfz Cfz
Dex
Dex
Dex
Dex
Len
>PR
CRd x 4
CRd x 4
CRd Maintenance
(Identical to initial CRd except no Cfz on
days 8, 9)
SCC
ASCT deferred
Dex, 40 mg/day days 1, 8, 15, and 22; 20 mg, cycles 58, and maintenance
1. Niesvizky R, et al. Blood (ASH Meeting Abstracts). 2009;114:Abstract 304.; 2. Martin T, et al, Presented at the 2010 Lymphoma and Myeloma Conference. New York.
10
CRd Frontline Study:
Updated Phase I Results
· MTD not reached
· MPD of Cfz 36 mg/m2, Len 25 mg, Dex 40 mg established as ph II dose
Best Response
2 cycles 4 cycles 8 cycles
Response, %
(n=33*)
(n=33)
(n=29)
(n=18)
sCR/CR/nCR
60
27
41
61
sCR
27
CR/nCR
33
VGPR
82
42
62
83
PR
97
97
97
100
*As of data cutoff : 28 February 2011
Jakubowiak AJ, et al. IMW 2011: Abstract P251
5
11
CRd Frontline Study:
Phase I experience
Welltolerated
· Low rate of neutropenia (8% all grades, 2% G3/4)
· no neutropenic fevers
· No significant decline of ANC or platelets in
consecutive cycles
· Very low rate of PN ( 11%, only grade 1 or 2)
Dose
· Extended tolerability
Modifications
n(%)
· Patients continue CRd maintenance for
Cfz
3 (8)
extended periods , most with no dose
Len
7 (20)
modification
Dex
3 (9)
Time to Event
· At a median followup of 9 months
· 100% of patients are free of progression, 100% alive
Phase II is expected to complete enrollment in the 12 months
Evaluation of other Cfz combinations is ongoing
Jakubowiak AJ, et al. IMW 2011: Abstract P251
12
Salinosporamide (NPI0052)
Unique features
H
New chemical class (nonpeptide based,
H O H
H
natural product)
O
N
O
Prolonged inhibition of all 3 proteolytic
O
H
activities
C H 3
Overcomes Btz resistance in preclinical
models
C l
Preliminary Clinical Data
· Decreases in Mprotein observed, including in pts refractory to Btz
· Prolonged SD seen, even at low doses
· Inhibition of proteasome activity at levels seen for effective doses of Btz
· Appears to have less neuropathy than Btz
· Enrollment continues to assess an alternate formulation and schedule.
Hofmeister CC, et al, J Clin Oncol. 2009;27:Abstract 8505.
6
13
MLN9708: Oral Proteasome Inhibitor
Similarities to bortezomib
· Boronic acidbased; reversibly inhibits the chymotryptic site
Unique features
· Orally bioavailable, hydrolyzes to active drug MLN2238
· More rapidly dissociates from the proteasome
· Greater tissue penetration
Preliminary Clinical Data
MTD at 2.0 mg/m2 given orally on Days 1,4, 8 and 11 of a 21day cycle
A partial response in 2 patients, and stable disease in 17 (71%)
Antitumor activity is reflected by duration of treatment
· 10 patients completed at least 5 cycles, 6 >10 cycles.
Toxicities are manageable
· The frequency and severity of peripheral neuropathy appeared low
Combination studies with Len and Dex in the upfront setting are now underway.
Richardson et al, Presented at the 2011 International Myeloma Workshop. Paris
14
Other Novel PIs in Clinical Studies
CEP18770
· Another boronic acidbased inhibitor
· Encouraging initial results reported
ONX 0912
· A potent, irreversible, orally bioavailable, peptide epoxyketone PI and
a structural analog of Cfz
· Currently undergoing clinical evaluation in a phase I trial in patients
with advanced solid tumors with plans for studies in MM.
7
15
Novel Proteasome Inhibitors:
Key Conclusions from Clinical Studies to Date
Encouraging early results showing unique clinical features of
individual PIs
Single agent (superior ?) activity
Carfilzomib shows high activity in relapsed and bortezomibnaïve pts
MLN9708 shows objective early evidence of response in heavily pretreated
patients
Emergence of ability to overcome bortezomib resistance
Improved tolerance
Carfilzomib shows very low rate of neuropathy, low rates of neutropenia
Emergence evidence of lower neuropathy for other agents including
MLN9708 and NPI0052
Very encouraging early experience with combinations
Cfz + Len + Dex (CRd) very active in relapsed
CRd is highly active in newly diagnosed MM
Compares favorably to other frontline regimens
8