VANTAGE 095: An International,
Multicenter, Open-Label Study of
Vorinostat (MK-0683) in Combination
With Bortezomib in Patients With
Relapsed or Refractory Multiple Myeloma
On behalf of the study investigators
David S. Siegel,1 Meletios Dimopoulos,2 Sung-Soo Yoon,3 Jacob P. Laubach,4
Jonathan L. Kaufman,5 Hartmut Goldschmidt,6 Donna Reece,7 Xavier Leleu,8
Simon Durrant,9 Fritz Offner,10 Michele Cavo,11 Arnon Nagler,12 Sundar
Jagannath,13 Thorsten Graef,14 Jennifer Houp,14 Linda Sun,14 Jason Howe,14
Sandra Wear,15 Kenneth C. Anderson4
1Hackensack University Medical Center, Hackensack, NJ, USA; 2Department of Therapeutics, University of Athens, Athens,
Greece; 3Seoul National University Hospital, Seoul, Korea; 4Dana-Farber Cancer Institute, Boston, MA, USA; 5Winship
Cancer Institute of Emory University, Atlanta, GA, USA; 6Universitätsklinikum Heidelberg, Heidelberg, Germany; 7Princess
Margaret Hospital, Toronto, Ontario, Canada; 8Centre Hospitalier Régional Universitaire de Lille, Lille, France; 9Royal
Brisbane and Women's Hospital, Brisbane, QLD, Australia; 10Universitair Ziekenhuis Gent, Gent, Belgium; 11"Seràgnoli"
Institute of Hematology, Azienda Ospedaliero-Universitaria S. Orsola-Malpighi, Bologna, Italy; 12The Chaim Sheba Medical
Center, Tel Hashomer, Israel; 13St. Vincent's Comprehensive Cancer Center, New York, NY, USA; 14Merck Research
Laboratories, Upper Gwynedd, PA, USA; 15Multiple Myeloma Research Consortium, Norwalk, CT, USA
Rationale for Vorinostat in
Relapsed/Refractory MM
· Despite the significant advances in MM treatment in the past decade, all
patients eventually relapse from successive treatment regimens with
progressively shorter response durations1
· Outcomes are poor for patients who received multiple therapies and
whose disease is relapsed and refractory following bortezomib and
lenalidomide
Estimated median survival of ~9 months2
Unmet medical need for new agents in this heavily pretreated patient population
· Epigenetic changes, such as acetylation of histone or nonhistone
proteins, are recognized as important factors in cancer development
· Vorinostat is a histone deacetylase (HDAC) inhibitor that blocks the
enzymatic activity of HDAC1, HDAC2, HDAC3, and HDAC6
Approved since 2006 for the treatment of cutaneous T-cell lymphoma
MM=multiple myeloma
1. Richardson PG et al. Blood. 2007;110(10):3557-3560. 2. Kumar S. et al. Haematologica. 2010;95:Abstract 0376.
1
Combined Data From Two Phase 1 Studies
of Vorinostat Plus Bortezomib
All patients (N=57, 54 evaluable)
Bortezomib refractory (N=15)
DCR: 93% / 93%
50%
CBR: 50% / 46%
47%
45%
43%
ORR: 39% / 33%
40%
35% 33%
35%
30%
25%
20%
13%
15%
11%
10%
7%
7%
4%
5%
n=19
n=5
n=6
n=2
n=23 n=7
n=4
n=1
n=2
0%
0%
CR
VGPR
PR
MR
SD
PD
DCR=disease control rate; CBR=clinical benefit rate; ORR=overall response rate; CR=complete response; VGPR=very good
partial response; PR=partial response; SD=stable disease; PD=progressive disease
Weber et al. Blood (ASH Annual Meeting) 2008;112:Abstr 871; Badros et al. Clin Cancer Res. 2009;15:5250-5257.
VANTAGE PN095: Study Design
Study population
Dosing schedule
Dexamethasone
(N=143)
(N=142)
(N=57/142)
Progressive disease
Bortezomib
required at study entry
Patients with PD or no
1.3 mg/m2 IV, Day 1, 4, 8, 11
Relapsed from 2 prior lines
change after 4 cycles
plus
of therapy
were permitted to add oral
Vorinostat
dexamethasone 20 mg on
· Refractory to bortezomib
400 mg QD, Day 114
the day of, and day after,
· Refractory to/ineligible for
each dose of bortezomib
THAL and/or LEN
(21-day cycle)
· Primary endpoint: ORRa
All patients who received treatment: N=142
· Secondary/exploratory endpoints: DOR, OS, PFSa, TTP, safety
All patients who received treatment: N=142
THAL=thalidomide; LEN=lenalidomide; IV=intravenous; QD=once daily; DOR=duration of response; OS=overall survival;
PFS= progression-free survival; TTP=time to progression
aAssessed by an Independent Adjudication Committee (IAC) according to European Group for Blood and Marrow Transplant (EBMT) criteria.
2
Patient Baseline Characteristics
Vorinostat + Bortezomib
Baseline Characteristic
(N=143)
Median age, years (range)
63 (3781)
Patients >65 years, n (%)
56 (39)
Median time since diagnosis, years (range)
4.7 (0.625.0)
ECOG 1, n (%)
122 (85)
Immunoglobulin class, %
IgG
58
IgA
24
IgM/D
3
Light chain disease
15
Median serum 2-microglobulin, mg/L
4.6
3.5 mg/L / >5.5 mg/L, %
72 / 44
Initial ISS stage I / II / III / unknown, %
24 / 27 / 34 / 15
ISS stage I / II / III (at screening), %
27 / 37 / 36
Baseline evaluation, %
Prior neuropathy,a %
56
CrCl (3060 mL/min)
30
Platelets (75,000100,000/mcL)
22
Hemoglobin (911 g/dL)
69
aBased on reported medical history.
Prior Therapies at Baseline
Vorinostat + Bortezomib
Prior Therapy
(N=143)
Prior lines of therapy, median (range)
4 (217)
4 prior lines of therapy, %
69
Prior therapies
100
Bortezomib, %
99
Immunomodulatory agent (IMiDs), %
85 / 71 / 4
Thalidomide / lenalidomide / pomalidomide, %
99
Corticosteroid, %
90
Alkylating agents, %
69
Anthracycline, %
74
Stem cell transplant, %
Refractory to last line of therapy, %
86
Nonresponsive (SD)
64
Progression or relapse within 60 days
22
Last prior regimen containing bortezomib and/or IMiDs, %
84
Refractory to bortezomib prior to enrollment
100
Refractory to 1 IMiDs prior to enrollment
87
Refractory to 2 IMiDs prior to enrollment
40
3
Drug Exposure
Vorinostat + Bortezomib
Exposure to Treatment
(N=142)
Median number of cycles (range)
4 (126)
Average number of cycles
6.2
Vorinostat dose reductions, %
46
Patients with 2 dose reductions, %
13
Median time to first dose reduction, days (range)
55 (1539)
Bortezomib dose reductions, %
54
Patients with 2 dose reductions, %
18
Median time to first dose reduction, days (range)
54 (1539)
Patients completing 6 cycles of treatment, %
39
Patients completing 8 cycles of treatment, %
27
Response Assessment (N=142)
IMWG response determined by IAC
DCR = 77%
50%
47%
45%
CBR = 31%; DOR = 6.3 months
40%
ORR = 17%
35%
30%
25%
20%
14%
15%
12%
10%
4%
5%
1%
0%
uCRa
VGPR
PR
MR
SD
Applying EBMT criteria:
ORR = 11%; DOR = 7.0 months
IAC=independent adjudication committee; IMWG=international myeloma working group; DOR=duration of response
auCR = unconfirmed CR due to missing bone marrow assessment.
4
Progression-Free Survival
Median PFS
95% CI
100
3.13 months
2.44.3
90
80
70
60
(%)
50
PFS
40
30
20
Vorinostat + BTZ
10
0 0
5
10
15
20
Time (months)
Number of subjects at risk
Vorinostat + BTZ
143
20
6
2
0
CI=confidence interval; BTZ=bortezomib
Overall Survival
Median OS
95% CI
100
11.2 months
8.514.4
90
1-year survival rate 44%
80
2-year survival rate 32%
70
60
(%)
50
OS
Vorinostat + BTZ
40
30
20
10
0 0
5
10
15
20
25
Time (months)
Number of subjects at risk
Vorinostat + BTZ
143
97
70
42
29
14
5
Efficacy Assessments: Subgroup Analysis
(IMWG criteria)
Vorinostat + Bortezomib
Baseline Factor
(EE population, N=136)
ORR, %
CBR, %
OS, months
Age at study entry
65 years (n=84)
17
30
10.9
>65 years (n=52)
19
37
11.7
ISS staging at study entry
I (n=37)
19
41
14.4
II (n=52)
23
35
10.8
III (n=47)
11
23
8.0
Prior lines of therapy
<5 (n=72)
18
35
10.9
5 (n=64)
17
30
11.4
Previous bortezomib regimens
(100% refractory to prior bortezomib)
1 (n=65)
18
37
11.7
>1 (n=71)
17
28
10.8
Previous IMiD regimens
(87% refractory to 1 IMiDs)
2 (n=85)
22
38
11.2
>2 (n=50)
10
24
10.9
Efficacy evaluable (EE) population: N=136; 6 patients missing post-baseline disease assessment
Safety Summary
Vorinostat + Bortezomib
Adverse experiences
(N=142)
n (%)
With AE
142 (100)
With serious AE
92 (65)
Discontinued due to an AE
27 (19)
GI-related
7 (5)
PN-related
2 (1)
Discontinued due to a serious AE
15 (11)
Discontinued due to progressive disease
79 (56)
Deaths (during treatment or safety follow-up)
24 (17)
Due to disease progression
18 (13)
Due to AE
6 (4)
Death due to drug-related AEa
1 (<1)
AE=adverse event; GI=gastrointestinal; PN=peripheral neuropathy
aConsidered possibly or probably related to study drug.
6
Adverse Events
Vorinostat + Bortezomib
Adverse event
(N=142)
Any Grade, % Grade 1-2, %
Grade 3-4, %
Hematologic (20%)
Anemia
52
14
38
Thrombocytopenia
70
2
68
Neutropenia
37
5
32
Non-hematologic (25%)
Nausea
57
50
7
Diarrhea
54
37
17
Fatigue
49
36
13
Vomiting
37
33
4
Decreased appetite
37
34
3
Pyrexia
27
23
4
Asthenia
25
15
10
Other AEs of interest
Neuropathya
22
20
2
Febrile neutropenia
4
0
4
aMedDRA preferred term, including neuropathy peripheral, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral
sensory neuropathy and neuralgia sensory neuropathy and neuralgia.
VANTAGE 095 Conclusions
· The combination of vorinostat + bortezomib is active in patients
whose disease is considered refractory to prior bortezomib and
IMiDs
17% ORR; 31% CBR by IMWG criteria
Median DOR of 6.3 months (CBR)
· Of clinical interest is the observed OS in this specific patient
population
Median OS of 11.2 months with a 2-year OS rate of 32%
· Combination is generally well tolerated in heavily pretreated
patients
27% of patients completed 8 cycles
· The combination of vorinostat + bortezomib may offer a new
treatment option for heavily pretreated, double-refractory myeloma
patients
7
Acknowledgments
Thank you to all of the patients and families who
contributed to this study
Additional participating study investigators and sites
Australia: J. Bashford, P. Coughlin, N. Horvath, I. Prosser, J. D'Rozario; Belgium: M. Delforge,
J. Van Droogenbroeck, J. Lemmens; Canada: M. Kovacs, L. Munik; France: J.P. Fermand;
Germany: H. G. Derigs, H. E. Dürk, R. Fenk, C. Scheid; Greece: K. Tsionos; Israel: D. BenYehuda, E. Naparstek;
Italy: S. Amadori; South Korea: J. S. Kim, S.J. Kim, J.H. Lee, J.J. Lee, C. K. Min, C.W. Suh;
Spain: A. Alegre, C. M. Chamorro; United Kingdom: J. Cavet;
United States: T. C. Gentile, P. Hari; S. Lonial, J. Wagner
All participating research nurses and data coordinators
Multiple Myeloma Research
Merck Research Laboratories
Contract Research Organization
Consortium
Lisa Lupinacci
Carmen Antonio
Sandra Wear
Jeffrey Yuan
Sarah Gopal
Louise Perkings
Katie Schneck
Yen-Chieh Cheng
Anne-Quinn Yong
Jason Howe
Martine Poelman
8