Vantage Myeloma
Myeloma Trials
Trials Progress
Progress Report
Vorinostat (Zolinza®) in combination with
bortezomib
1
O
H
N
OH
Scientific Background
N
O
H
Vo
V rinostat (s
(suberoylanilide
lanilide
hydroxamic acid)
· Vorinostat: Histone deacetylase
y
inhibitor
­ Broad inhibition: inhibits class I and class II HDAC
enzymes
­ First i
- n-class HDAC inhibitor approved by USA
USA h
l
ea th
lth
authority
­ Single-agent activity in peripheral T-cell lymphoma
­ Phase 1 Myeloma: objective responses observed in
patients resistant to bortezomib when administered
Vorinostat + bortezomib
· Badros et al. Haematologica 2008; 93 (S1): 0642
· Weber et al, ASH 2009
2
VORINOSTAT + BORTEZOMIB: SYNERGISTIC ACTIVITY
Blockade of ubiquinated protein catabolism at 2 different points in the pathway
Blockade of protein catabolism leads to
accumulation of misfolded proteins
Protein
myeloma cell death
Ub
Ub
Protein aggregates
(toxic)
Dual inhibition of
Ub
Ub
Ub
proteasome
Ub
26S proteasome
(VELCADE)
d
an
HDAC6
Bortezomib
aggresome
Ub
Ub
(ZOLINZA) prevents
Vo
V rinostat
o
compensatory survival
survival
HDAC6
mechanisms
dynein
Ub
Ub
Ly
L sosome
y
Aggresome
HDAC6
Ub Ub
Ub Ub
dynein
Ub
Ub
Microtubule
Autophagy
Hideshima et al. Clin Cancer Res 2005;11:8530 -8533
Catley et al. Blood 2006;108:3441-3449
3
Vorinostat + bortezomib in MM
Two Phase 1 multicenter trials (1 sponsored by Merck + 1 conducted
by NCI): vorinostat + bortezomib
· 34 and 23 patients were enrolled, respectively
· As a result of these studies the recommended dose of vorinostat is
400 mg QD in combination with
with standard
standard doses of bortezomib
· 7 and 8 patients, respectively were REFRACTORY to bortezomib
­ Of these, 4/7 and 3/8 patients
,p
had a response
p
to the
combination of vorinostat and bortezomib
· Vorinostat plus bortezomib was generally well tolerated
These findings supported the initiation of the VANTAGE clinical trial
program in multiple myeloma
4
VANTAGE studies in multiple myeloma
·
The VANTAGE program for multiple myeloma includes 2 pivotal
studies:
­
PN088 is an ongoing Phase III, multi-center, randomized, double-
blind (with in house blinding) study of ZOLINZA® in combination
with bortezomib in
in patients with multiple
multiple myeloma
myeloma (MM) who have
received 1 to 3 prior treatment regimens.
­
PN095 is an ongoing Phase IIb, multi-center, open-lbl
label t
s udy of
ZOLINZA® in combination with bortezomib in patients with relapsed
and refractory multiple myeloma who have received therapy with at
least 2 prior treatment regimens,
g, and who
­
are also refractory to bortezomib
­
and refractory/ineligible for at least one IMiD.
5
VANTAGE: Study Design
Vorinostat 400 mg daily
Rest
R
perid
iod
Placebo (PN088 only)
Bortezomib
1.3 mg/m2
Si
Screening
Day -21
14
8
11
14
21
21-day cycle
R = RANDOMIZED
6
Where Are We Now?
VANT
V
AGE
ANT
088
VANT
V
AGE
ANT
095
34 / 34
Countries active
13 / 13
210
Sites active
67
332 / 742
enrolled
106 / 142
~Nov-10
1st Interim analysis
Jan-10
7
As of May 2010
VANTAGE Clinical Trials:
PN088 Safety Analysis
(June 2010)
()
PN088: as the trial remains blinded, all data are provided with both
treatment arms combined
(data cut-off 5-Feb-2010)
8
Patient Accounting: Disposition 088
Number (%) of Patients
Tr
T eated
172 (99%)
Discontinued
52 (30%)
Who Died
8 ( 5%)
Dt
Dea h
th during treatment
2(
2 ( 1%)
1%)
Death during follow-up
6 ( 4%)
Death associated with study drug
0
With Drug-Related (DR) Adverse Events
124 (72%)
With Serious Adverse Events
51 (30%)
With Serious DR Adverse Events
12 ( 7%)
Primary Reason for Discontinuation
Adverse Event
19 (11%)
Withdrawal by Subject
13 ( 8%)
Progressive Disease
20 (12%)
9
PN088: data cutoff 5Feb2010
Baseline: Clinical Characteristics
N = 173
Age (years)
Medi
dian (Minimum, M
i
ax
)
mum
61 (38, 81)
Sex
Male
95 (55%)
Female
78 (45%)
()
Geographic Region
Asia
52 (30%)
Europe
74 (43%)
North America
19 (11%)
Other (AU, NZ, S.Af, Mx)
28 (16%)
ECOG Performance Status
0
65 (39%)
1
89 (53%)
2
15 ( 9%)
9%)
10
PN088: data cutoff 5Feb2010
Baseline: Clinical Characteristics
N = 173
Type of myeloma
IgG
11
116 (67%)
(67%)
IgA
40 (23%)
Other (light chain myeloma)
15 ( 8%)
Light chain
Kappa: Lambda
64% : 32%
Prior Regimens
Regimens
Median = 2
1
48%
2
27%
3
24%
Prior Bone Marrow Transplant
74 (43%)
11
PN088: data cutoff 5Feb2010
Prior Multiple Myeloma Drug Therapies
Total
N = 173
Bortezomib
42 (24%)
Cyclophosphamide
73 (42%)
Dexamethosone
145 (84%)
Doxorubicin
70 (41%)
Lenalidomide
22 (13%)
Melphalan
69 (40%)
Prednisone
25 (15%)
Thalidomide
87 (%
(50 )
%)
Vincristine Sulfate
84 (49%)
PN088:
~Half of patients received at least one IMiD
Thalidomide 50%, lenalidomide 13%
24% of patients received
received prior
prior bortezomib; patients must
must have had
at least an MR to prior bortezomib-based therapy
12
Patients with Specific Adverse Events
(Incidence >= 10%; N=172)
N=172)
All Grades
Grade 3-5
N%
N %
N%
N %
Blood and Lymphatic System Disorders
73 (42%)
46 (27%)
Anaemia
30 (17%)
8 (5%)
Neutropenia
31 (18%)
19 (11%)
Th
b
rom
i
ocytopen a
44 (26%)
30 (17%)
Gastrointestinal Disorders
106 (62%)
18 (11%)
Constipation
32 (19%)
1 (<1%)
Diarrhoea
52 (30%)
()
10 (6%)
()
Nausea
65 (38%)
6 (4%)
Vomiting
35 (20%)
4 (2%)
General Disorders
81 (47%)
14 (8%)
Fatigue
40 (23%)
8(
8 5%)
(5%)
Pyrexia
29 (17%)
1 (<1%)
13
Patients with Specific Adverse Events
(Incidence >= 10%; N=172)
All Grades
Grade 3-5
N %
N %
Metabolism and Nutrition Disorders
54 (31%)
9 (5%)
Decreased Appetite
35 (20%)
1 (<1%)
Musculoskeletal and Tissue Disorders
44 (26%)
6 (4%)
Back Pain
18 (11%)
1 (<1%)
Nervous System Disorders
78 (45%)
13 (8%)
Neuropathy Peripheral
Peripheral
20 (12%)
6(
6 4%)
(4%)
Peripheral Sensory Neuropathy
14 (8%)
0
Skin and Subcutaneous Disorders
32 (19%)
0
Rash
17 (10%)
0
14
PN088 Conclusions
APEX /
Grade 3-4 toxicity
PN0881
Velcade arm2
Thrombocytopenia
17%
30%
Neutropenia
11%
11
14%
Anemia
5%
10%
Neuropathy Peripheral /
4% / 0%
14%
Peripheral Sensory
Sensory Neuropathy
Diarrhea
6%
7%
Nausea / Vomiting
4 / 3%
2 / 3%
Asthenia / Fatigue
Fatigue
3/
3 / 4%
4%
12%
· The adverse event profile of the PN088 population appears to
be similar to the Velcade® Package Insert
· Adverse events of potential concern (cardiotoxicity for HDAC
inhibitors; interstitial pneumonitis for proteasome inhibitors)
were not notable
· No Grade 5 drug related AE/SAE were reported
1 Data cut-off 5-Feb-2010
15
2 Richardson et al, NEJM 2005 352:2487
VANTAGE Clinical Trials:
PN095 Interim Efficacy and Safety Analysis
January 2010 / March 2010
16
Phase IIb: VANTAGE 095 (N=142)
· An international, multicenter, open-label phase IIb study of vorinostat
in combination with bortezomib for patients
p
with relapsed
p
and
refractory multiple myeloma who are also
­ Refractory to prior bortezomib
­ Refractory/ineligible for at
at least
least one IMiD (thalidomide and/or
and/or lenalidomide)
· Efficacy endpoints:
­ Primary: ORR (CR + PR) by IAC using the EBMT criteria
­ S
d
econ ary: PFS, OS
OS, ORR
ORR onset
d
an d
bili
ura
ty
· Planned enrollment of 142 patients:
­ Final analysis once 29 patients obtain ORR by IAC (ORR 20%)
· Planned interim analysis
­ Nonbinding futility stopping guideline is 5 or fewer obtain ORR
17
Patient Accounting: Disposition 095
Number (%) of Patients
Treated
83 (98%)
Di
ti
scon nued
39 (46%)
Who Died
6 ( 7%)
Death during treatment
3 ( 4%)
()
Death during follow-up
3 ( 4%)
Death associated with study drug
0
With Drug-Related (DR)
(DR) Adverse Events
Events
62 (75%)
With Serious Adverse Events
36 (43%)
With Serious DR Adverse Events
11 (13%)
Primary Reason for Discontinuation
Adverse Event
13 (15%)
Withdrawal by Subject
2 ( 4%)
Progressive Disease
21 (25%)
Physician Decision
3 ( 4%)
18 PN095: data cutoff 26Mar2010
Baseline: Clinical Characteristics
N=83
Age (years)
Median (Minimum, Maximum)
()
61 (45, 77)
()
Sex
Female
35 (41%)
Male
50 (59%)
Geographic Region
Asia (SK)
27 (32%)
Europe
33 (39%)
North America
21 (25%)
Other (AU)
4 ( 5%)
ECOG Performance Status
Status
0
13 (16%)
1
60 (72%)
29 (11%)
3
1(
1 ( 1%)
1%)
19 PN095: data cutoff 26Mar2010
Baseline: Clinical Characteristics
N=83
Type of myeloma
IgG
55 (66%)
IgA
18 (22%)
Other (light chain myeloma)
6 ( 7%)
Light chain
Kappa: Lambda
63% : 37%
Pi
Prior R
i
eg mens
Md
Me i
dian = 4 5
.
2
10 (13%)
3
13 (16%)
4
17 (21%)
5
10 (13%)
6-8
21 (25%)
9-17
9 (11%)
Pi
Prior Bone Marrow T
l
ransp
t
an
60 (71%)
Current ISS staging
I
21 (29%)
II
22 (31%)
III
29 (40%)
20 PN095: data cutoff 26Mar2010
Differences in PN095 and PN088
· PN095 patients are more heavily pretreated
· "Time since Initial Myeloma Diagnosis" for PN095
patients is longer
· More PN095 patients have received prior bone
marrow transplant
· PN095 patients have baseline blood
blood count values
(WBCs, RBCs, platelets) that are lower ("less
marrow reserve") and are therefore more likely to
experience hematologic toxicity
21
Baseline: Prior Therapies
· PN095: All patients confirmed refractory to prior
bt
bortezomib
ib
· PN095: All patients received at least one IMiD
­ Thalidomide only:
29 (37%) patients
­ Lenalidomide only:
7 ( 9%) patients
­ Thalidomide and lenalidomide:
42 (54%) patients
22 PN095: data cutoff 26Mar2010
Patients with Specific Drug-Related AEs
(Incidence >= 10%)
()
All Grades
Grade 3-5
N %
N %
Nausea
50 (29%)
6 (4%)
Thrombocytopenia
40 (23%)
26 (15%)
Diarrhoea
35 (20%)
9 (5%)
Fatigue
33 (19%)
8 (5%)
Neutropenia
29 (17%)
18 (11%)
Decreased appetite
27 (16%)
1 (<1%)
Vomiting
26 (15%)
4 (2%)
Neuropathy peripheral
20 (12%)
6 (4%)
Constipation
17 (10%)
1 (<1%)
23
PN095 Efficacy (Interim analysis)
· Futility bar was passed with 7/43 responders
· All objective responses were confirmed (at least 6 weeks)
24
Safety: Grade 3-4 Adverse Events ( 10%)
PN095
PN088
Patients in Safety Population
83
172
· Blood and lymphatic system disorders
­ Anemia
16 (19%)
8 ( 5%)
­ Nt
Neutropenia
10 (12%)
19
19 (11%)
(11%)
­ Thrombocytopenia
37 (45%)
30 (17%)
· Gastrointestinal disorders
­ Diarrhea
13 (16%)
10 ( 6%)
· General disorders and admin site conditions
­ Fatigue
9 (11%)
8 ( 5%)
25 PN095: data cutoff 26Mar2010
PN095 Conclusions
· PN095 population experienced a higher
incidence of
of toxicity,
toxicity, likely due to having been
exposed to a greater number of previous anti-
myeloma regimens (including BMT) and more
advanced disease.
· Close safety monitoring is recommended in this
population, with attention to supportive care,
h
prop
l
y
ti
ac c therapy as
d
nee ed, dose
reductions implemented per protocol and
patient education
· Early efficacy read out indicates clinical value of
this combination in this difficult bortezomib
refractory population
26 PN095: data cutoff 26Mar2010
Questions?
27