8133
Update on Vantage Program to Assess Combined Vorinostat (V) and Bortezomib (B)
in Patients (pts) With Relapsed and/or Refractory (RR) Multiple Myeloma (MM)
Sundar Jagannath,1 David Siegel,2 Roman Hajek,3 Meletios Dimopoulos,4 Sung-Soo Yoon,5 Sagar Lonial,6 Thorsten Graef,7 Lisa Lupinacci,7 David Reiser,7 Kenneth C. Anderson8
1St Vincent's Catholic Medical Center, New York, NY, USA; 2Hackensack University Medical Center, Hackensack, NJ, USA; 3Faculty of Medicine MU and University Hospital Brno, Brno, Czech Republic; 4Department of Therapeutics, University of Athens,Athens, Greece;
5Seoul National University Hospital, Seoul, Korea; 6Winship Cancer Institute, Emory University School of Medicine,Atlanta, GA, USA; 7Merck Research Laboratories, Upper Gwynedd, PA, USA; 8Dana-Farber Cancer Institute, Boston, MA, USA
INTRODUCTION
Secondary
Figure 1. Study Design for Vantage 088 and 095
Table 1. Baseline Patient and Disease Characteristics
Interim Futility Analysis (Vantage 095)
· Based on review of efficacy and safety data as of March 2010, the
Relapsed/
Vantage 088
Vantage 095
· The futility analysis threshold was exceeded with 7 confirmed
independent data monitoring committee (DMC) advised continuation
· Multiple myeloma (MM) remains largely incurable, with most patients
· Secondary objectives for both studies include assessments of safety
refractory
088
Characteristic
(N=173)*
(N=83)*
MM
Vorinostat 400 mg QD
responders (PR) in the first 43 patients evaluated.
without modification for Vantage 095.
eventually relapsing or becoming refractory to treatment.
(adverse event [AE] profile), time to progression, and OS. In addition, PFS
1
Median age, y (range)
61 (3881)
61 (4577)
and ORR are included as secondary endpoints in the 095 and 088 studies,
Rest
R
Sex, n (%)
· ORR rate in less heavily pretreated patients (<6 prior regimens) was 33%
· Patients who are refractory or are ineligible for treatment with novel
period
respectively.
Men
95 (55)
50 (59)
(7 PRs out of 21 patients).
therapies have poor prognosis, with median overall survival (OS) of
Placebo (only 088)
Relapsed/refractory
Women
78 (45)
35 (41)
CONCLUSIONS
MM, refractory to
6 months.
095
2 Thus, new treatment options are urgently needed for this
Exploratory
bortezomib and
Geographic region, n (%)
Safety
other therapies
Bortezomib
· Preliminary data were presented for 2 large trials
patient population.
· To evaluate patient-reported outcomes on treatment with vorinostat and
1.3 mg/m2
Asia
52 (30)
27 (32)
· Overall, treatment has been tolerable with no major safety signals
investigating combined vorinostat and bortezomib
· In patients with relapsed/refractory MM, lower rates of response
bortezomib using the European Organization for Research and Treatment
Europe
74 (43)
33 (39)
observed in either study.
Screening
North America
19 (11)
21 (25)
treatment in RR MM patients, with primary objectives
are seen in patients with an increasing number of prior treatment
of Cancer (EORTC) QLQ-C30 and EORTC QLQ-MY20 for quality of life
Day 21
1
4
8
11
14
21
· Vantage 088: Of the 172 patients in the safety population, 124 (72%)
Other
28 (16)
4 (5)
being assessment of PFS (Vantage 088) or ORR
regimens,2 providing a context for the anticipated outcome to new
and EuroQoL EQ-5D for health utility
21-day cycle
experienced treatment-related AEs (Table 2).
ECOG performance status, n (%)
(Vantage 095).
treatment options.
· To determine the proportion of patients who achieve either a very
PN095 only Patients with PD after 2 cycles or no change after 4 cycles are
· In total, 12 (7%) patients experienced treatment-related serious AEs (SAEs).
permitted to add treatment with oral dexamethasone 20 mg on the
0
65 (39)
13 (16)
· Continuation of Vantage 095 without modifications was
· Vorinostat is an oral histone deacetylase inhibitor (HDACi) that
good PR or better (International Myeloma Working Group criteria) or
day of, and day after, each dose of bortezomib.
1
89 (53)
60 (72)
· There were 19 (11%) discontinuations due to AEs or SAEs.
recommended by the independent DMC after a review of
alters gene expression and protein activity. Approved in the United
a minimal response (MR; European Blood and Marrow Transplantation
2
15 (9)
9 (11)
MM=multiple myeloma; PD=progressive disease; QD=once daily; R=randomization.
3
1 (1)
Table 2. Frequency of AEs in Vantage 088 and 095 Studies
efficacy and safety data; the interim analysis for Vantage
States in 2006 for the treatment of patients with cutaneous T-cell
[EBMT] criteria)
Current ISS staging, n (%)
Patients, n (%)
088 (N=172)
095 (N=83)
088 will be conducted when 126 PFS events have occurred
lymphoma who have progressive, persistent, or recurrent disease
Assessments
I
62 (36)
21 (29)
Experienced 1 treatment-related AE
124 (72)
62 (75)
in the trial.
during or after receiving two systemic therapies,3 vorinostat is the
METHODS
· Response to treatment was assessed using EBMT criteria.10
II
72 (42)
22 (31)
Experienced grade 34 AEs (10%)
first-in-class HDACi and has been administered to >2050 patients
· Safety assessments were conducted throughout the study, and AEs were
III
39 (23)
29 (40)
Blood and lymphatic system disorders
· Combined treatment with vorinostat and bortezomib
· Vantage 088: Phase III randomized double-blind study (N=742 planned
since initial approval.4
graded according to the National Cancer Institute Common Terminology
Myeloma type, n (%)
Anemia
8 (5)
16 (19)
in Vantage 095 has demonstrated clinical activity and
accrual) of bortezomib plus vorinostat or placebo in MM patients aged
IgG
116 (68)
55 (66)
Neutropenia
19 (11)
10 (12)
· Preclinical data suggest that the addition of HDAC inhibitors can
Criteria for Adverse Events, version 3.0.
apparent tolerability in a highly pretreated (median
18 years with progressive disease after 13 prior treatment regimens
IgA
40 (23)
18 (22)
Thrombocytopenia
30 (17)
37 (45)
synergistically increase the apoptotic activity of the proteasome
of 4.5 prior regimens), bortezomib-refractory patient
· Vantage 088:The first formal interim analysis (with futility/efficacy
Other (light chain myeloma)
15 (9)
6 (7)
Gastrointestinal disorders
inhibitor bortezomib in MM cells and other tumor types; in addition,
· Vantage 095: Phase IIb international open-label study (N=142 planned
population.
stopping rules) is planned when 25% of PFS events (ie, n=126 events) have
Prior anticancer regimens, n (%)
Diarrhea
10 (6)
13 (16)
pretreatment with vorinostat sensitizes MM cells to bortezomib-
accrual) of vorinostat plus bortezomib in RR MM patients aged 18 years
occurred.
23
87 (51)
23 (29)
General disorders
· Common treatment-related AEs observed for
induced proteasome inhibition.
who had received
4
17 (21)
5-7
2 prior treatment regimens
Fatigue
8 (5)
9 (11)
the combination of vorinostat and bortezomib
· Vantage 095:An interim futility analysis was conducted when 43 patients
5
10 (13)
Experienced 1 treatment-related SAE
12 (7)
11 (13)
· Results from 2 phase I studies have demonstrated that combined
Inclusion/Exclusion Criteria
were consistent with the AE profile associated
had been enrolled; study termination would occur if 5 patients had
68
21 (25)
AE=adverse event; SAE=serious adverse event.
treatment with vorinostat and bortezomib (± dexamethasone)
· Vantage 088: Patients who had previously received bortezomib must have
with treatment with either agent when used
achieved at least a PR.
917
9 (11)
resulted in an objective response rate (ORR) of approximately 40%
achieved MR, PR, or complete response (CR; eg, not bortezomib-refractory).
Median (range)
2 (13)
4.5 (217)
· For Vantage 088, the following grade 3 or 4 treatment-related SAEs
alone, and included nausea, diarrhea, anorexia,
in relapsed/refractory (RR) MM patients, including those who were
History of bone marrow transplant, n (%)
74 (43)
60 (71)
were experienced by 1 patient each: generalized edema, left ventricular
thrombocytopenia, and fatigue.
· Vantage 095: Patients must have been refractory to bortezomib and
RESULTS
refractory to bortezomib.
ECOG=Eastern Cooperative Oncology Group; Ig=immunoglobulin; ISS=International Staging System.
8,9
dysfunction, neuralgia, acute pancreatitis, pyrexia, vomiting, arthritis, bone
relapsed while taking, refractory to, intolerant of, or ineligible for other
Patients
*Because of missing data, numbers do not add up to study number (N) for all categories.
pain, renal failure, dyspnea exertional, cognitive disorder, and lethargy. No
· Coupled with the unmet patient need, these preliminary data
MM therapies including at least 1 IMiD (thalidomide or lenalidomide).
One patient received more than 3 prior regimens.
· As of April 2010, 286 patients had been enrolled in Vantage 088.
grade 5 treatment-related AEs were reported.
REFERENCES
provided the rationale for 2 global multicenter clinical trials (Vantage
· Patients had Eastern Cooperative Oncology Group performance status 2.
· As of February 2010, 173 patients had been enrolled, 172 patients had
· As of April 2010, 100 patients had been enrolled in Vantage 095.
· Vantage 095: Of the 83 patients in the safety population, 62 (75%)
088 and 095) to assess efficacy and safety of treatment with
1. Reece DE, et al. Leuk Lymphoma. 2008;49:1470-1485.
· Exclusion criteria included prior allogeneic bone marrow transplantation
been treated, and 52 patients had discontinued.
· As of March 2010, 85 patients had been enrolled, 83 patients had been
experienced treatment-related AEs (Table 2).
2. Kumar S, et al. Blood (ASH Annual Meeting Abstracts). 2009;114;2878.
vorinostat plus bortezomib in RR MM patients.
3. ZOLINZA® (vorinostat). Full Prescribing Information, Merck & Co., Inc.,Whitehouse Station, NJ,
or any planned bone marrow transplantation within 4 weeks of study
· Primary discontinuation reasons were progressive disease (n=20),
treated, and 39 patients had discontinued.
· In total, 11 (13%) patients experienced treatment-related SAEs.
2009.
entry, prior treatment with an HDAC inhibitor or inability to tolerate
AEs (n=19), and patient withdrawal (n=13).
· Primary discontinuation reasons were AEs (n=13), patient withdrawal
· There were 13 (15%) discontinuations due to AEs or SAEs.
4. Data on File. Merck, Sharp, and Dohme, a subsidiary of Merck & Co., Inc.,Whitehouse Station, NJ.
2010.
OBJECTIVES
bortezomib, acute systemic infection requiring treatment, acute diffuse
· Patients had received a median of 2 prior regimens: 80 had received
(n=2), physician decision (n=3), and progressive disease (n=21).
· Grade 3 or 4 treatment-related SAEs in Vantage 095 included
5. Carew JS, et al. Cancer Lett. 2008;269(1):7-17.
infiltrative pulmonary disease, pericardial disease, or infection with HIV or
1 regimen, 46 had received 2 regimens, and 41 had received 3 regimens
· This population represents an extremely difficult-to-treat population
thrombocytopenia (n=3 patients); anemia and diarrhea (n=2 each); and
6. Mitsiades CS, et al. Proc Natl Acad Sci U S A. 2004;101(2):540-545.
Primary
7. Pei XY, et al. Clin Cancer Res. 2004;10(11):3839-3852.
hepatitis B or C.
(Table I).
of MM patients; all had failed 2 prior therapy regimens and were
asthenia, malnutrition, metabolic acidosis, nausea, pneumonia, renal failure,
8. Badros A, et al. Clin Cancer Res. 2009;15(16):5250-5257.
· Vantage 088:To determine the progression-free survival (PFS) of
· More than half of the patients had received 1 IMiD: 50% thalidomide,
refractory to bortezomib.
Study Design
tumor lysis syndrome, and vomiting (n=1 each). No grade 5 treatment-
9. Weber DM, et al. Blood (ASH Annual Meeting Abstracts). 2008;112:871.
10. Bladé J, et al. Br J Haematol. 1998;102(5):1115-1123.
vorinostat plus bortezomib, compared with placebo plus bortezomib,
and 13% lenalidomide.
· Patients had received a median of 4.5 prior regimens (range, 217;
related AEs were reported.
· Patients received intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8, and
in MM patients who had received 13 prior treatment regimens
· 25% of patients had previously received bortezomib.
Table 1).
· The Vantage 095 study represents a more advanced MM population
11 and oral vorinostat 400 mg (or matching placebo in 088) once daily on
· Vantage 095:To determine the ORR (proportion of patients achieving at
· The threshold for the first interim analysis (ie, 126 PFS events) has not
· All patients had received 1 IMiD: thalidomide only (n=29, 37%),
(ie, median of 4.5 prior regimens); thus the increased toxicity seen relative
days 114 of each 21-day cycle (Figure 1).
least a partial response [PR]) to vorinostat plus bortezomib in RR MM
yet been reached.
lenalidomide only (n=7, 9%), or both thalidomide and lenalidomide
to Vantage 088 is not unexpected.
Funding Source:This study was funded by Merck, Sharp and Dohme, a subsidiary of Merck & Co., Inc.
· Treatment continued until disease progression, unacceptable toxicity, or
(n=42, 54%).
patients who had received at least 2 prior treatment regimens and are
withdrawal of consent.
considered to be refractory to bortezomib and refractory/ineligible for
American Society of Clinical Oncology
2010 Annual Meeting
1 immunomodulatory drug (IMiD)
June 48, 2010
Chicago, IL