Transcript Document

Novel Therapies for Myeloma
A. Keith Stewart
Scottsdale, Arizona
Rochester, Minnesota
Jacksonville, Florida
Disclosure of Potential Conflicts of Interest
Honoraria: Celgene, Millenium
Research grants: Millenium
Consultant: Proteolix
A “Gold Rush” in Myeloma Pre-clinical
Drug Testing
>200 drugs reported in preclinical
studies (~$30,000,000)
>200 drugs reported in
preclinical studies
~30 - 40 trial results reported
3 agents with known significant single
agent activity – all arise from known
active drug classs
Single Agent Activity of 39 Drugs Tested in Myeloma
Single Agent Activity of 39 Drugs Tested in Myeloma
Inactive Drugs
Active Drugs
Pomalidomide (CC4047) plus low-dose dexamethasone (Pom/Dex)
is highly effective therapy in relapsed multiple myeloma
MQ Lacy, S Hayman, M Gertz, J Allred, S Mandrekar, A Dispenzieri,
S Zeldenrust, S Kumar, P Greipp, J Lust, S Russell, F Buadi, R Kyle,
PL Bergsagel, R Fonseca, V Roy, J Mikhael, AK Stewart, and SV Rajkumar
Mayo Clinic
Scottsdale, Arizona
Rochester, Minnesota
Jacksonville, Florida
Molecular Structure of Thalidomide,
Lenalidomide and Pomalidomide
O
O
O
N
N
O
O
N
O
O
H
N
O
NH2
Thalidomide
100-200 mg/d
Lenalidomide
15-25 mg/d
Neuropathy
Constipation
Sedation
DVT
Myelosuppression
Skin rash
DVT
O
H
N
N
NH 2
O
Pomalidomide
1-4 mg/d
Structurally similar, but functionally different both qualitatively
and quantitatively
O
Study design & treatment
• Phase II trial, 60 patients
• A confirmed response is defined to be a CR, PR or VGPR as
assessed by the International Myeloma Working Group
Uniform Response criteria.
• Starting Dose:
• Pomalidomide - 2mg p.o. daily days 1-28
• Dexamethasone - 40mg p.o. days 1, 8, 15 & 22
• Aspirin - 325mg p.o. days 1-28
Best Response
Response
CR
Median follow-up
7 months
N =60
3 (5%)
VGPR
17 (28%)
PR
18 (30%)
SD
15 (25%)
PD
6 (10%)
NE
1 (2%)
ORR 63%
CR +VGPR
33%
Responses in patients refractory
to other novel agents
Refractory to
N
Bortezomib
10
1 (10%)
2 (20%)
3 (30%)
4 (40%)
0
6 (60%)
Lenalidomide
20
0
1 (5%)
7 (35%)
9 (45%)
3 (15%)
8 (40%)
Thalidomide
16
0
2 (12.5%)
4 (25%)
6 (37.5%)
4 (25%)
6 (37.5%)
CR
VGPR
PR
SD
PD
RR*
Patient 2, 67 year old female
M-spike 3.5
CRD started
Bortezomib
M-spike 2.6
Pom/dex, M-spike 2.9
Relapsing on
CRD
Bortezomib
Melphalan,
Pred
Conclusions
• The combination of pomalidomide and low dose
dexamethasone is highly active in the treatment
of relapsed/refractory multiple myeloma.
• Toxicity has been manageable and consists
primarily of myelosuppression with neutropenia.
• Future directions include phase II trial of
pomalidomide and dexamethasone for
lenalidomide-refractory and bortezomib –
refractory patients
Updated Results of Bortezomib-Naïve Patients in
PX-171-004, An Open-Label, Phase 2 Study of
Single-Agent Carfilzomib in Patients with Relapsed
or Refractory Multiple Myeloma
Luhua Wang, MD, David Siegel, MD, Jonathan L. Kaufman, MD,
Keith Stewart, MD, Andrzej J. Jakubowiak, MD, PhD, Melissa Alsina, MD,
Vishal Kukreti, MD, FRCPC, Nizar J Bahlis, MD, Kevin T. McDonagh, MD,
Andrew Belch, MD, Michael Sebag, MD, PhD, Nashat Gabrail,MD,
Mai H. Le, MD, Mark K Bennett, PhD, Lori Kunkel, MD,
Michael Kauffman, MD, PhD, Robert Z Orlowski, M.D., Ph.D., Ravi Vij, MD
and The Multiple Myeloma Research Consortium (MMRC)
Carfilzomib:
Carfilzomib is a new, selective and irreversible proteasome
inhibitor with pre-clinical anti-tumor activity.
Responses seen in Phase I Myeloma trials.
Tetrapeptide
Ketoepoxide
PX-171-004 Carfilzomib Phase 2 Study Design
Population: Multiple Myeloma, relapsed after 1-3 prior therapies
CFZ administration: 20 mg/m2 IV bolus; maximum 12 cycles
Premedication: Hydration, Dexamethasone 4 mg during Cycle 1
% proteasome
inhibition
D1 D2
Week:
D8 D9
D15 D16
0
Rest period
(12 days)
28-day
cycle
80
1
2
3
4
QDx2 weekly for 3 weeks
Primary endpoint: Overall response rate (ORR = CR + VGPR + PR)*
Secondary endpoints: DOR, PFS, TTP, OS, Safety
*IMWG response criteria
Carfilzomib: Dose Escalation to 27 mg/m2
100
15.8
% of subjects
80
31.6
60
40
47.4
20
0
VGPR
PR
MR
SD
PD
N (%)
Evaluable
population
19 (100)
CR
0 (0)
VGPR
1 (5)
PR
9 (47)
MR
0 (0)
SD
6 (32)
≥PR : 53%
≥MR : 53%
≥SD : 84%
5.3%
Bortezomib
Naive
(N = 19)
ORR (> PR) = 53%
Disease Control in 84%
PX-171-003: Response Summary (N=39)
Seven subjects excluded from response analysis:
• Serum free light chain only (4)
• Received < 1 cycle of therapy (2)
• No baseline value (1)
*
% of subjects
50
40
30
CBR=26%
20
10
0
PR
MR
50% of responses
occurred at 2 weeks
SD
PD
Most Commonly Reported Adverse Events
Adverse Event*, 1
Fatigue
Nausea
Dyspnea
Cough
Anemia
Diarrhea
Pyrexia
Peripheral Edema
Thrombocytopenia
Upper Respiratory
Infection
Overall
n (%)
40 (68)
27 (46)
25 (42)
22 (37)
21 (36)
18 (31)
18 (31)
18 (31)
15 (25)
> Grade 3
n (%)
7 (12)
0 (0)
3 (5)
0 (0)
4 (7)
1 (2)
0 (0)
1 (2)
7 (12)
15 (25)
1 (2)
*All AEs reported in >25% patients
1Includes
both related and non-related
Data through Oct 2009
Peripheral Neuropathy is Infrequent and Mild
50
% of subjects (N=90)
There were no reports of Grade 4
peripheral neuropathy
40
30
Only 1 patient was discontinued for
peripheral neuropathy
20
12%
10%
10
2%
0
All Grades
(n=11)
Gr 1 or 2
(n=0)
Gr3
(n=1)
Neuropathy AEs
Data through October 2009
*Grade Based on physical assessment at screening (NCI-CTC scale)
Carfilzomib Conclusions: Ph 2 Relapsed MM
 Single agent carfilzomib is highly active in relapsed patients
– 57% response rate in BTZ-naïve patients
– 26% CBR in Refractory disease
 CFZ achieves durable disease control with continued dosing
– Median TTP 11.1 mos in BTZ-naïve patients
– Median TTP 8.3 mos in BTZ-exposed patients
 Few > grade 3 Aes
 Peripheral neuropathy is not a treatment-limiting toxicity with CFZ
Carfilzomib: Future Directions
 Dose escalation to 27 mg/m2
 Combination with Lenalidomide and Dexamethasone
 Registrational Development
– single arm monotherapy Phase 2 in refractory pts
completed
– Randomized Phase 3 lenalidomide/dexamethasone +/- CFZ
planned for 2010
Many drugs in trials – some current examples
AUY922
TAK901 / MLN8237
CEP070 / MLN9708
TKI258 / MFGR1877S
SCH727965
Panobinostat
Monoclonals : CD38
BHQ880
t(4;14) 15% of Myeloma
Hypothesis
Pharmacologic abrogation of tyrosine kinase signaling by
FGFR3 in MM cells will result in a tumour-specific
cytotoxicity
TKI-258 (Dovitinib)
MFGR1877S
BM restricted plasmacytosis in Vk*MYC mice
CD138
wt
spleen
BM
Vk*MYC
spleen
BM
B220
Chesi et al, Cancer Cell, February 2008
Monoclonal Protein
Placebo
Dexamethasone
Melphalan
Bortezomib
Revlimid
%decrease from d=0
{
Day
0
14
0
14
0
14
0 14
0 14
Conclusions
 Three new active drugs with many more being
tested in clinical trials
 New Mouse models and target selection may
result in higher success rate in clinic
 Future trials will likely focus on individualized
therapy for different types of myeloma