Journal of Hematology & Oncology
BioMed Central
Open Access
Review
Vorinostat in solid and hematologic malignancies
David Siegel*1, Mohamad Hussein2, Chandra Belani3, Francisco Robert4,
Evanthia Galanis5, Victoria M Richon6, José Garcia-Vargas6, Cesar SanzRodriguez7 and Syed Rizvi6
Address: 1Hackensack University Medical Center, Hackensack, NJ, USA, 2H. Lee Moffitt Cancer Center, Tampa, FL, USA, 3Penn State Cancer
Institute, Hershey, PA, USA, 4University of Alabama, Birmingham, AL, USA, 5Mayo Clinic College of Medicine, Rochester, MN, USA, 6Merck
Research Laboratories, Upper Gwynedd, PA, USA and 7Merck Research Laboratories, Madrid, Spain
Email: David Siegel* - dsiegel@humed.com; Mohamad Hussein - mhussein@celgene.com; Chandra Belani - cbelani@hmc.psu.edu;
Francisco Robert - pacorobertuab@cs.com; Evanthia Galanis - galanis.evanthia@mayo.edu; Victoria M Richon - vrichon@epizymebio.com;
José Garcia-Vargas - jose_garcia-vargas@merck.com; Cesar Sanz-Rodriguez - cesar_sanzrodriguez@merck.com;
Syed Rizvi - syed_rizvi@merck.com
* Corresponding author
Published: 27 July 2009
Journal of Hematology & Oncology 2009, 2:31
doi:10.1186/1756-8722-2-31
Received: 29 May 2009
Accepted: 27 July 2009
This article is available from: http://www.jhoonline.org/content/2/1/31
© 2009 Siegel et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Vorinostat (Zolinza®), a histone deacetylase inhibitor, was approved by the US Food and Drug
Administration in October 2006 for the treatment of cutaneous manifestations in patients with
cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following
two systemic therapies. This review summarizes evidence on the use of vorinostat in solid and
hematologic malignancies and collated tolerability data from the vorinostat clinical trial program.
Pooled vorinostat clinical trial data from 498 patients with solid or hematologic malignancies show
that vorinostat was well tolerated as monotherapy or combination therapy. The most commonly
reported drug-related adverse events (AEs) associated with monotherapy (n = 341) were fatigue
(61.9%), nausea (55.7%), diarrhea (49.3%), anorexia (48.1%), and vomiting (32.8%), and Grade 3/4
drug-related AEs included fatigue (12.0%), thrombocytopenia (10.6%), dehydration (7.3%), and
decreased platelet count (5.3%). The most common drug-related AEs observed with vorinostat in
combination therapy (n = 157, most of whom received vorinostat 400 mg qd for 14 days) were
nausea (48.4%), diarrhea (40.8%), fatigue (34.4%), vomiting (31.2%), and anorexia (20.4%), with the
majority of AEs being Grade 2 or less. In Phase I trials, combinations with vorinostat were generally
well tolerated and preliminary evidence of anticancer activity as monotherapy or in combination
with other systemic therapies has been observed across a range of malignancies. Ongoing and
planned studies will further evaluate the potential of vorinostat in combination therapy, including
combinations with radiation, in patients with diverse malignancy types, including non-small-cell lung
cancer, glioblastoma multiforme, multiple myeloma, and myelodysplastic syndrome.
Histone Deacetylase Inhibition with Vorinostat
as a Target in Oncology
Advanced or refractory malignancy remains an area of
high unmet medical need as patients often relapse and
curative therapy is elusive. The mainstay of treatment is
generally cytotoxic chemotherapy which can have limited
efficacy and is often associated with significant toxicity;
there is a need for novel agents that are not only effective
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but also well tolerated. In particular, there has been
increasing interest in targeted therapies which work at an
epigenetic level to influence gene expression and ultimately control tumor growth and proliferation. Histone
deacetylase (HDAC) inhibitors represent one such class of
new mechanism-based anticancer drugs [1].
Modifications to histones influence chromatin structure,
and ultimately gene transcription, including those coding
for tumor suppressor proteins. One of the key histone
modifications that controls gene transcription is acetylation, which is regulated by two opposing enzymatic activities (histone acetyltransferases [HATs] and HDACs) [1].
Histone acetylation leads to an open chromatin structure,
and allows access to transcription binding sites. Although
histones are one of the targets of HATs and HDACs, many
nonhistone proteins, including transcription factors,
tubulin and heat shock protein 90, can also be regulated
by acetylation [2,3].
HDACs have been shown to be overexpressed in human
cancers, such as gastric, prostate and colon cancer, and are
involved in the regulation of transcription with recruitment by oncogenic transcription factors [4]. Therefore,
the inhibition of HDACs is a rational target for the development of novel anticancer therapy. To date, 18 HDACs
have been identified in mammalian cells, which are categorized into different classes, based on their homology to
yeast deacetylases [5]. By inhibiting these enzymes, HDAC
inhibitors permit chromatin to assume a more relaxed
conformational state, thereby allowing transcription of
genes involved in tumor suppression, cell-cycle arrest, cell
differentiation, and apoptosis (Figure 1[4]) [6].
A variety of HDAC inhibitors are in clinical development
and are being assessed in a number of different cancer
indications [7]. There are several chemical families among
the HDAC inhibitors, including short-chain fatty acids
(butyrate, valproic acid), hydroxamates (vorinostat, tri-
Vorinostat
HDAC
Histone acetylation
Anthracycline
Radiation
Cisplatin
Decitabine
Bexarotene
Protein acetylation
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
p21WAF1
TS
VEGF
Ac
Ac Ac
17AAG
STAT5 genes
p53 genes
BCL6 genes
5FU
Flavopiridol
Bevacizumab
Hsp90
raf1
ErbB1 Trastuzumab
ErbB2
Taxanes
Cellcycle arrest and apoptosis
a
The sites of action of other antitumor agents are also shown
Figure 1 mechanism of action of vorinostat in inducing tumor cell-cycle arrest and apoptosisa [4]
Proposed
Proposed mechanism of action of vorinostat in inducing tumor cell-cycle arrest and apoptosisa [4]. HDAC, histone deacetylase; TS, thymidylate synthase; VEGF, vascular endothelial growth factor; 17-AAG, 17-allylamino-17-demethoxygeldanamycin; 5-FU, 5-fluorouracil. Reprinted by permission from Macmillan Publishers Ltd: Richon VM. Cancer biology:
mechanism of antitumour action of vorinostat (suberoylanilide hydroxamic acid), a novel histone deacetylase inhibitor. Br J
Cancer 2006; 95 (Suppl 1): S2–S6, copyright 2006.
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chostatin A, LBH-589, PXD-101), cyclic tetrapeptides
(depsipeptide), and benzamides (MS-275, MGCD-0103).
Vorinostat (Zolinza®; Merck & Co., Inc., Whitehouse Station, NJ, USA) was the first HDAC inhibitor licensed for
clinical use and has been shown to inhibit the activity of
class I and II HDACs, in particular HDAC1, HDAC2,
HDAC3 (class I), and HDAC 6 (class II) at low nanomolar
concentrations [4,5,8]. In addition to chromatin histone
proteins that are involved in the regulation of gene expression, HDACs have many nonhistone protein targets
including transcription factors and proteins that regulate
cell proliferation, migration, and death [5]. For example,
HDAC 6, which is predominantly cytosolic, has been
shown to have roles in microtubule stability and function
via the acetylation of α-tubulin [9], in the regulation of
heat-shock protein 90 [10], and in the formation of aggresomes of ubiquitinylated proteins [11].
Vorinostat Monotherapy for Solid and
Hematologic Malignancies
Vorinostat is the first HDAC inhibitor approved for the
treatment of cancer: in October 2006, the US Food and
Drug Administration granted approval to vorinostat for
the treatment of cutaneous manifestations of cutaneous Tcell lymphoma (CTCL) in patients with progressive, persistent or recurrent disease on or following two systemic
therapies [12]. This approval was based on a pivotal Phase
IIb multicenter trial of vorinostat monotherapy, which
included 74 patients with persistent, progressive or recurrent, stage IB or higher CTCL who had received at least two
prior systemic therapies including bexarotene [13]. The
objective response rate was 30% and the most common
drug-related adverse events (AEs) were diarrhea (49%),
fatigue (46%), nausea (43%), and anorexia (26%). Most
of these AEs were Grade 2 or lower but 21/74 patients
(28%) had drug-related Grade 3/4 AEs, the most common
being fatigue (5%), pulmonary embolism (5%), thrombocytopenia (5%), and nausea (4%). Similar results were
observed in a second, smaller Phase II study including 33
patients with CTCL who were refractory to or intolerant of
conventional therapy [14]. In this study, 8/33 patients
(24%) achieved a partial response and the most common
drug-related AEs were fatigue (73%), thrombocytopenia
(54%), diarrhea (49%), nausea (49%), dysgeusia (46%),
dry mouth (35%), and weight loss (27%). The most common drug-related Grade 3 or 4 AEs were thrombocytopenia (19%) and dehydration (8%). Overall, these studies
showed that vorinostat as monotherapy was effective in
advanced CTCL and had an acceptable safety profile. Vorinostat is included in the National Comprehensive Cancer
Network Clinical Practice Guidelines in Oncology™ for
non-Hodgkin's lymphoma (NHL), where it is listed as a
systemic therapy option for patients with mycosis fungoides/Sézary syndrome who have failed multiple treat-
http://www.jhoonline.org/content/2/1/31
ments with local and skin-directed therapy or who have
unfavorable prognostic features [15].
Phase I studies have indicated that vorinostat monotherapy has an acceptable safety profile in patients with a
variety of solid and hematologic malignancies [16-25].
Similarly, Phase II studies in patients with head and neck
cancer [26], diffuse large B-cell lymphoma (DLBCL) [27],
glioblastoma multiforme (GBM) [28], hormone-refractory prostate cancer [29], breast cancer [30], NHL [31],
Hodgkin's lymphoma [32], non-small-cell lung cancer
(NSCLC) [33], breast, colorectal or NSCLC [34], epithelial
ovarian or primary peritoneal carcinoma [35], and myelodysplastic syndrome [36], have also shown that vorinostat is well tolerated, with preliminary activity as
monotherapy against NHL and GBM [28,31].
In the Phase II study of vorinostat monotherapy in
patients with GBM, 66 patients who had received ≤ 1 prior
chemotherapy regimen for progressive/recurrent GBM,
and who were not undergoing surgery, were treated with
200 mg vorinostat bid on Days 1–14 every 3 weeks [28].
The primary efficacy endpoint was met; nine of the first 52
patients were progression-free at 6 months, and the
median overall survival was 5.7 months. As in the earlier
CTCL studies, the majority of AEs were Grade 2 or lower;
the most common Grade 3 or 4 AEs were thrombocytopenia (22%), fatigue (17%), neutropenia (8%), dehydration
(6%), and hypernatremia (5%). In a subgroup of five
patients with surgical recurrent GBM who received vorinostat prior to surgery, immunohistochemical analysis of
paired baseline and post-vorinostat samples showed
increased acetylation levels of histones H2B and H4, and
histone H3 following vorinostat therapy in four of five
and three of five patients, respectively. Microarray analysis
of RNA extracted from the same paired samples revealed
changes in the expression pattern of genes regulated by
vorinostat, such as upregulation of E-cadherin (p = 0.02).
These results suggest that the dose and schedule of vorinostat employed in this Phase II trial had a biologic effect on
glioblastoma tumors, affecting target pathways in GBM.
The authors of this study concluded that vorinostat has
single-agent activity in GBM and is well tolerated.
In the other Phase II monotherapy study that demonstrated preliminary clinical activity, of 37 enrolled
patients with relapsed or refractory follicular, marginal
zone or mantle cell lymphoma, five patients achieved a
complete response and five a partial response [31].
While there has not been clear evidence of QTc prolongation due to vorinostat in either preclinical or clinical studies to date, isolated clinical events of QTc prolongation in
previous vorinostat studies have been observed, and QTc
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prolongation has been reported for other HDAC inhibitors [37,38]. However, in a Phase I randomized, placebocontrolled, crossover study conducted in 25 patients with
relapsed or refractory advanced cancer, administration of
a single supratherapeutic dose of vorinostat (800 mg) did
not prolong the QTcF interval (monitored over 24 hours)
[39]. The upper limit of the 90% confidence interval for
the placebo-adjusted mean change-from-baseline of vorinostat was less than 10 ms at every time point for all 24
patients included in the QTcF analysis. For the vorinostat
and placebo groups, there were no observed QTcF changes
from baseline values >30 ms and only one patient experienced a QTcF interval >450 ms (seen following both vorinostat and placebo administration).
gistic or additive activity in cell lines from a wide range of
solid and hematologic malignancies [4,5], including
NSCLC [42-46], multiple myeloma (MM) [47-49], and
leukemia [45,50-61]). In various models, treatment with
vorinostat in combination resulted in synergistic apoptotic effects with associated increases in reactive oxygen
species and mitochondrial injury, caspase and poly (ADPribose) polymerase activation. Synergistic activity has also
been demonstrated in vivo; in one study in orthotopic
human pancreatic tumors, the addition of vorinostat to
bortezomib, and the resulting inhibition of HDAC 6 and
disruption of aggresome formation, led to much higher
levels of apoptosis and significantly reduced pancreatic
tumor weight compared with either agent alone [62].
The acceptable safety profile of vorinostat observed in
these studies, together with the monotherapy activity in
some tumor types, provide a good foundation for the use
of vorinostat in combination regimens.
Some preclinical data also indicate that the activity of
vorinostat in combination with radiation may be promising [63-66]. Vorinostat is to be tested in the adjuvant setting of GBM in combination with radiotherapy and
temozolomide [67], and further trials are ongoing or
planned in brain metastases and other indications where
radiotherapy is used alone and in combination.
Biologic Rationale for Vorinostat Use in
Combination with Other Therapies
Combination chemotherapy or chemoradiotherapy are
frequently employed in preference to single-agent therapy
to maximize treatment efficacy, but can be associated with
increased toxicity. Vorinostat has a different mechanism
of action compared with many other antineoplastic
agents; therefore, it may be able to improve clinical efficacy in combination with other systemic agents where
there are no or minimal overlapping toxicities. In addition, it has been hypothesized that the mechanism of
action of HDAC inhibitors, through the acetylation of key
lysine residues in core histones leading to a more relaxed
chromatin configuration, may allow enhanced access to
the DNA by another antineoplastic agent that directly
interacts with DNA (e.g. cisplatin) resulting in synergistic
activity [40].
Combination strategies may also help to overcome potential mechanisms of drug resistance to HDAC inhibitors
[41]. These include other chromatin alterations such as
DNA methylation, which together with hypoacetylation is
thought to cooperate to induce gene silencing. Thus, the
combination of HDAC inhibitors with hypomethylating
agents, such as azacitidine and decitabine, is rational. Any
protection against the cellular oxidative stress induced by
HDAC inhibitors, such as proteins that participate in the
stress response to oxidative damage, has also been postulated as a mechanism of resistance to HDAC inhibitors. In
this case, the combination of HDAC inhibitors with other
agents that also induce oxidative damage, such as bortezomib or doxorubicin, could help to overwhelm the stress
response.
Numerous preclinical studies of vorinostat in combination with other cancer therapies have demonstrated syner-
On the basis of these and other studies, vorinostat in combination is being evaluated in clinical trials in patients
with a variety of solid and hematologic malignancies.
Vorinostat in Combination for Advanced Solid
Tumors
A number of Phase I studies have been undertaken to
determine the recommended Phase II dose of vorinostat
in combination with other established chemotherapy
agents in patients with advanced or refractory solid
tumors [68-74] (Table 1[68-74]). In one of these studies,
in which vorinostat was combined with carboplatin and
paclitaxel, particularly promising activity was noted in
patients with advanced NSCLC, with 10/19 patients
(53%; 18 chemonaïve) experiencing a partial response
and 4/19 (21%) stable disease [68]. In comparison, treatment with carboplatin-paclitaxel of chemonaïve patients
with advanced NSCLC results in response rates of approximately 15–25% [75-77]. The combination was generally
well tolerated. Grade 3/4 toxicity was predominantly
hematologic: of 28 treated patients, 2 patients experienced Grade 4 febrile neutropenia, and 8 and 14 patients
experienced Grade 3 and 4 neutropenia, respectively;
although this was more than expected from carboplatinpaclitaxel alone, with rates of Grade 4 neutropenia of 17–
43% previously reported [75-77], there was no definite
relationship found between the dose and schedule of vorinostat and the incidence of Grade 3/4 neutropenia. Doselimiting toxicities (DLTs) were Grade 3 vomiting (one
patient) and Grade 4 febrile neutropenia (one patient)
and the recommended Phase II dose for vorinostat in
combination with carboplatin-paclitaxel was 400 mg qd
for 14 days every 3 weeks. In another study, vorinostat was
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Table 1: Phase I Results of Vorinostat in Combination Therapy in Patients with Advanced Solid Tumors
Tumor Type
No. Pts Treatment
Advanced solid
22
Advanced solid
20
Advanced colorectal 21
Advanced solid
28
Refractory solid
22
Advanced solid
26
Malignant glioma
19
Summary of Results
Ref
Vorinostat + pemetrexed + cisplatin
DLTs: fatigue (2), dehydration (2), neutropenia (1), cerebral
ischemia (1) DVT (1)
19 patients evaluable for response: 1 CR, 1 PR, 11 SD, 6 PD
Vorinostat 300 mg qd for 7/21 days was tolerable with cisplatin 75
mg/m2 + pemetrexed 500 mg/m2
Vorinostat + doxorubicin
DLTs: thrombocytopenia (1), fatigue (1), nausea/vomiting, and
anorexia (1)
Response: 1 PR, 3 SD, 11 PD, 5 NE
Tolerated dose of vorinostat higher than approved single-agent
dose in patients with hematologic malignancies
Vorinostat +
DLTs: fatigue (1), fatigue and diarrhea (1), fatigue, anorexia, and
5-FU/LV + oxaliplatin
dehydration (1)
Response: 11 SD (5 confirmed) of 21 evaluable patients
Recommended dose: vorinostat 300 mg bid on Days 1–7 + 5-FU/LV
+ oxaliplatin on Day 4 every 14 days
Vorinostat + carboplatin + paclitaxel DLTs: vomiting (1), febrile neutropenia (1)
Response: 11 PR, 7 SD in 25 evaluable patients
(of 19 pts with NSCLC [18 chemonaïve], 10 [53%] had a PR)
Phase II regimen: vorinostat 400 mg qd on Days 1–14 + carboplatin
AUC 6 mg/mL × min + paclitaxel 200 mg/m2
Vorinostat + bortezomib
DLTs: fatigue (3), hyponatremia (1), elevated ALT (1)
MTD (step A): vorinostat 400 mg qd on Days 1–14 + bortezomib
1.3 mg/m2 on Days 1, 4, 8, and 11 of a 21-day cycle
Clinical activity observed: 1 PR >9 months in a patient with
refractory soft tissue sarcoma
Vorinostat + capecitabine
DLTs: diarrhea (1), fatigue (2), nausea/vomiting (1)
Response: 4 PR (3 confirmed), 18 SD, 4 PD
Recommended Phase II regimen: vorinostat 300 mg qd +
capecitabine 1000 mg/m2 bid
Vorinostat + temozolomide
DLTs: thrombocytopenia (2), fatigue (3), nausea (1)
MTD: vorinostat 300 mg qd on Days 1–14 + temozolomide 150
mg/m2/day on Days 1–5 every 28 days
[70]
[71]
[74]
[68]
[72]
[73]
[69]
DLT, dose-limiting toxicity; ALT, alanine aminotransferase; MTD, maximum tolerated dose; PR, partial response; DVT, deep vein thrombosis; CR,
complete response; PR, partial response; SD, stable disease; PD, disease progression; NE, not evaluable; NSCLC, non-small-cell lung cancer; AUC,
area under the curve; 5-FU/LV, 5-fluorouracil/leucovorin.
combined with doxorubicin without exacerbation of doxorubicin toxicity, with a tolerated vorinostat dose of 400
mg bid dosed on Days 1–3 every week [71].
The results of disease-specific Phase I vorinostat combination studies in patients with malignant gliomas [69] or
colorectal cancer [74] have also been published (Table
1[68-74]). In patients with malignant gliomas treated
with escalating doses of vorinostat plus temozolomide,
DLTs were Grade 3 thrombocytopenia, Grade 3 nausea,
and Grade 4 thrombocytopenia each reported in one
patient, and Grade 3 fatigue reported in three patients
[69]. The recommended Phase II dose for vorinostat in
combination with temozolomide was 300 mg qd on Days
1–14 every 28 days.
Overall, the data of vorinostat in combination regimens
for the treatment of a variety of advanced solid tumors
demonstrate that, when used with other chemotherapy
agents, vorinostat can be well tolerated and the prelimi-
nary anticancer activity noted supports the conduct of disease-specific Phase II studies. A range of ongoing studies
will further evaluate the role of vorinostat in combination
therapy in a variety of advanced solid tumors; these
include Phase I/II studies with vorinostat in combination
in patients with advanced breast cancer, small-cell lung
cancer, and NSCLC, and Phase II studies in combination
with tamoxifen or carboplatin and paclitaxel in patients
with advanced breast cancer or in combination with carboplatin and paclitaxel in patients with advanced NSCLC
[67].
Vorinostat in Combination for Hematologic
Malignancies
Vorinostat also has potential in combination with chemotherapy or other biologic agents as treatment for hematologic malignancies. The combination of vorinostat plus
the proteasome inhibitor bortezomib has been investigated in two Phase I studies in heavily pretreated patients
with advanced relapsed or refractory MM [78,79] (Table
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Table 2: Phase I Results of Vorinostat in Combination Therapy in Patients With Hematologic Malignanciesa
Tumor Type
No. Pts
Treatment
Summary of Results
Ref
Relapsed multiple myeloma
23
Vorinostat + bortezomib
[78]
Relapsed, refractory or poor prognosis
acute leukemia or refractory anemia with
excess blasts-2
22
Vorinostat + flavopiridol
(bolus or 'hybrid' infusion
schedules)
Advanced acute leukemia
20
Vorinostat + idarubicin
Relapsed or newly-diagnosed acute
myelogenous leukemia or myelodysplastic
syndrome
70
Vorinostat + decitabine
(concurrent or sequential
regimens)
Relapsed, refractory or poor prognosis
leukemia
31
Vorinostat + decitabine
Relapsed or refractory multiple myeloma
18
Vorinostat + lenalidomide +
dexamethasone
Myelodysplastic syndrome and acute
myeloid leukemia
28
Vorinostat + azacitidine
Advanced multiple myeloma
34
Vorinostat + bortezomib
Acute myeloid leukemia
27
Vorinostat + decitabine
DLTs: prolonged QT interval (1), fatigue (1)
MTD vorinostat 400 mg qd on Days 4–11 +
bortezomib 1.3 mg/m2 on Days 1, 4, 8, and 11 every
21 days
Response: 2 VGPR, 7 PR, 10 SD
(21 evaluable patients)
DLTs: infectious colitis with sepsis (1 [bolus]) and
atrial fibrillation (1 ['hybrid'])
MTD: not yet reached on vorinostat 200 mg tid given
in a 'hybrid' schedule with flavopiridol at 30/30 mg/m2
(load/infusion) on Days 1 and 8 of a 21-day cycle,
identification of the MTD and recommended phase II
dose is ongoing
Response: 10 patients experienced some clinical
benefit (20 evaluable patients)
DLTs: myelosuppression, encephalopathy, and
dysphagia
2 CR and 2 complete marrow responses observed in
patients who had failed previous anthracycline-based
therapy
Recruitment ongoing at vorinostat 400 mg tid for 3
days + idarubicin 12 mg/m2 for 3 days every 14 days
DLT: prolonged QT interval (1 [sequential])
Response: concurrent (n = 34), 7 CR, 2 PR, 2 HI, 12
SD; sequential (n = 36), 3 CR, 2 HI, 16 SD
MTD not reached
Last cohort: vorinostat 400 mg qd for 14 days (Days
1–14 concurrent or Days 6–19 sequential) +
decitabine 20 mg/m2/day on Days 1–5 every 28 days
DLTs: pulmonary embolism and diarrhea (1)
Response: 1 CR, 4 significant reduction in bone
marrow blasts, 4 SD, 14 PD, 7 NE
(30 evaluable patients)
Last cohort: decitabine 25 mg/m2 daily for 5 days
followed by vorinostat 200 mg tid for 14 days
DLTs: none yet reported
MTD: not yet reached, DLT evaluation ongoing in
patients enrolled to vorinostat 400 mg qd for 14 days
(Days 1–7 and 15–21), combined with lenalidomide
25 mg qd for 21 days, and dexamethasone 40 mg/day
(Days 1, 8, 15, and 22) every 28 days
Response: 1 CR, 4 PR, 1 MR, 5 SD
(15 evaluable patients)
DLTs: not reported
Response: 9 CR, 2 incomplete CR, 7 HI, 2 SD
(21 evaluable patients)
Last cohort: azacitidine 55 mg/m2/day on Days 1–7 +
vorinostat 300 mg bid on Days 3–5 every 28 days
DLTs: transient AST elevation (1), thrombocytopenia
(1)
MTD not yet reached, the maximum administered
dose was vorinostat 400 mg qd on Days 1–14 +
bortezomib 1.3 mg/m2 on Days 1, 4, 8, and 11 every
21 days.
Response: 12 PR, 6 MR, 13 SD (33 evaluable patients).
In 17 evaluable patients who had received prior
bortezomib therapy, 6 PR, 4 MR, 7 SD
DLT: fatigue (1)
Response: 1 incomplete CR, 1 morphologic leukemiafree (without neutrophil recovery), 3 PR (25 evaluable
patients)
MTD not reached: maximum dose vorinostat 200 mg
bid on Days 1–21 + decitabine 20 mg/m2/day on Days
1–5 every 28 days
[81]
[82]
[83]
[84]
[87]
[85]
[79]
[86]
aOnly trials including at least 15 patients are reported in this table.
DLT, dose-limiting toxicity; AST, aspartate aminotransferase; MTD, maximum tolerated dose; PR, partial response; MR, minimal response; SD, stable
disease; VGPR, very good partial response; nCR, near complete response; PD, progressive disease; CR, complete response; NE, not evaluable; HI,
hematologic improvement.
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2[78-87]). In one of these studies, one patient receiving
vorinostat 400 mg qd on Days 1–14 plus bortezomib 0.9
mg/m2 on Days 1, 4, 8, and 11 every 21 days experienced
a DLT of Grade 3 transient aspartate aminotransferase elevation and one patient receiving vorinostat 400 mg qd
plus bortezomib 1.3 mg/m2 experienced a DLT of Grade 4
thrombocytopenia [79]. The most common (≥ 10% of
patients) Grade 3/4 drug-related AEs were thrombocytopenia (38%) and fatigue (12%). Dose escalation was successfully completed and the maximum tolerated dose
(MTD) was not reached. The maximum administered
dose was vorinostat 400 mg qd on Days 1–14 plus bortezomib 1.3 mg/m2 on Days 1, 4, 8, and 11 every 21 days.
In the second of these studies, MTD was established at 400
mg qd on Days 4–11 plus bortezomib 1.3 mg/m2 on Days
1, 4, 8, and 11 every 21 days, with DLTs of Grade 3 prolonged QT interval and Grade 3 fatigue each reported in
one patient [78].
Efficacy appeared to be similar in these two studies: in the
first study, of 33 patients evaluable for efficacy, 12 had a
partial response, 6 had a minimal response (overall 55%
response), and 13 had stable disease; 2 patients experienced progressive disease [79]. In the second study, which
included more heavily pretreated patients (median
number of prior regimens 7 versus 3), 9/21 patients
(43%) had a response, 10 had stable disease, and 2 had
disease progression [78]. In contrast, only modest singleagent activity was observed with vorinostat in patients
with relapsed/refractory MM, with 1/10 evaluable patients
having a minimal response and 9/10 stable disease [25].
Preliminary data from Phase I studies have shown that
vorinostat is well tolerated when combined with cytarabine and etoposide for the treatment of advanced acute
leukemia and high-risk myelodysplastic syndrome [80],
with flavopiridol in refractory or high-risk acute myeloid
leukemia [81], or in combination with lenalidomide and
dexamethasone in patients with relapsed or refractory
MM [87]. Other ongoing Phase I studies of vorinostat
combinations in patients with hematologic malignancies
have also shown that combinations with idarubicin,
decitabine or azacitidine are well tolerated [82-86] and
have suggested potential anticancer activity of vorinostat
in combination with idarubicin, in patients with
advanced leukemia [82], decitabine, in patients with
advanced leukemia [84], acute myeloid leukemia [83,86],
or myelodysplastic syndrome [83], or azacitidine in
patients with myelodysplastic syndrome or acute myeloid
leukemia [85] (Table 2[78-87]). Again, the tolerability
profile and preliminary anticancer activity support the
continuing investigation of combinations of vorinostat
with other chemotherapy agents in disease-specific Phase
II studies. Ongoing clinical trials will further evaluate the
role of vorinostat in combination therapy in hematologic
http://www.jhoonline.org/content/2/1/31
malignancies, such as MM, leukemia, and lymphoma
[67].
Safety and Tolerability of Vorinostat – Overall
Experience from the Vorinostat Clinical Trial
Program
Analysis of combined safety data from the vorinostat clinical trial program of Phase I and II trials demonstrate that
vorinostat has an acceptable safety and tolerability profile
either as monotherapy or combination therapy in patients
with a variety of solid and hematologic malignancies. At a
cut-off date of April 2008, collated data were available for
341 patients who received vorinostat as monotherapy for
either solid tumors (mesothelioma, head and neck, renal,
thyroid, laryngeal, breast, colorectal, NSCLC, and gastric
cancers) or for hematologic malignancies (acute myeloid
leukemia, chronic lymphocytic leukemia, or chronic myeloid leukemia, NHL [including CTCL, peripheral T-cell
lymphoma, DLBCL, and follicular lymphoma], Hodgkin's
disease, myelodysplastic syndrome or MM). Of these
patients, 156 patients were treated at a dose of 400 mg qd
(the current FDA-approved dose for patients with CTCL).
The most commonly reported drug-related AEs were
fatigue (62%), nausea (56%), diarrhea (49%), anorexia
(48%), and vomiting (33%) (Table 3). Grade 3/4 drugrelated AEs included fatigue (12%), thrombocytopenia
(11%), dehydration (7%), and decreased platelet count
(5%). Three drug-related deaths (ischemic stroke, tumor
hemorrhage, unspecified) were observed.
Similarly, collated safety data from 157 patients who
received vorinostat (most commonly at 400 mg qd for 14
days) in combination with other systemic therapies in the
vorinostat clinical trial program were available for analysis (cut-off date of April 2008). Patients received vorinosTable 3: Drug-Related Adverse Events Occurring in ≥ 15% of
Patients Who Received Vorinostat Monotherapy in the
Vorinostat Clinical Trial Program (Data Cut-Off April 2008)
Adverse Event
Fatigue
Nausea
Diarrhea
Anorexia
Vomiting
Blood creatinine increased
Weight decreased
Hyperglycemia
Thrombocytopenia
Platelet count decreased
Hemoglobin decreased
Constipation
Dysgeusia
No. (%) of Patients (N = 341)
All Grades
Grade 3 or 4
211 (61.9)
190 (55.7)
168 (49.3)
164 (48.1)
112 (32.8)
88 (25.8)
86 (25.2)
79 (23.2)
71 (20.8)
65 (19.1)
60 (17.6)
60 (17.6)
59 (17.3)
41 (12.0)
14 (4.1)
14 (4.1)
17 (5.0)
5 (1.5)
2 (0.6)
4 (1.2)
10 (2.9)
36 (10.6)
18 (5.3)
10 (2.9)
3 (0.9)
0 (0.0)
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http://www.jhoonline.org/content/2/1/31
tat in combination with other systemic therapies for the
treatment of advanced cancer, MM, CTCL, and NSCLC. In
combination, the most commonly reported drug-related
AEs were nausea (48%), diarrhea (41%), fatigue (34%),
vomiting (31%), and anorexia (20%) (Table 4). The most
common Grade 3/4 events were fatigue (13%), thrombocytopenia (10%), neutropenia (8%), diarrhea (6%), and
nausea (5%). There was one drug-related AE leading to
death due to hemoptysis in one patient with NSCLC.
Overall, vorinostat was well tolerated, with the majority of
AEs being Grade 2 or less, and vorinostat was not associated with the levels of hematologic toxicity commonly
found with other antineoplastic agents. Furthermore,
dose modifications were usually not required in the
majority of patients who received vorinostat as monotherapy or in combination therapy.
SR, JGV, and CSR are employees of Merck & Co., Inc. VMR
was a founder of Aton Pharma Inc. and an employee of
Merck & Co., Inc., and is now employed by EpiZyme Inc.
MH is now employed by the Celgene Corporation.
Merck employees may own shares or stock options of
Merck & Co., Inc. CB is a consultant for Merck & Co., Inc.
DS, EG, and FR have no relevant financial disclosures to
declare.
Authors' contributions
All authors (DS, MH, CB, FR, EG, VMR, SR, JGV and CSR)
participated in drafting and editing the manuscript and all
authors read and approved the final manuscript.
Acknowledgements
We thank Dr Annette Smith, from Complete Medical Communications,
who provided medical writing support funded by Merck.
Conclusion
Vorinostat is generally well tolerated and has shown
potential anticancer activity against a variety of hematologic and solid tumors, particularly in combination therapy, as well as in monotherapy. As monotherapy,
combined data from the vorinostat clinical trial program
demonstrate that vorinostat has an acceptable safety and
tolerability profile, with the most common Grade 3/4 AEs
being fatigue (12%) and thrombocytopenia (11%).
Although the tolerability data from Phase I trials of vorinostat in combination are limited, the individual trial
data suggest that the combinations are also generally well
tolerated, and this appears to be substantiated by pooled
safety data from the vorinostat clinical trial program.
Despite concerns, the available data suggest that there do
not appear to be any unexpected toxicities when vorinostat is combined with other antineoplastic agents. These
preliminary clinical results from Phase I and II trials support the rationale for combining vorinostat with other
chemotherapy agents and/or radiotherapy as a means of
increasing the therapeutic index of cancer therapy.
Table 4: Drug-Related Adverse Events Reported by ≥ 15% of
Patients Who Received Vorinostat Combination Therapy in the
Vorinostat Clinical Trial Program (Data Cut-Off April 2008)
Adverse Event
Competing interests
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