The

Oncologist ®

Regulatory Issues: FDA

FDA Approval Summary: Vorinostat for Treatment of Advanced
Primary Cutaneous T-Cell Lymphoma

BHUPINDER S. MANN, JOHN R. JOHNSON, MARTIN H. COHEN, ROBERT JUSTICE, RICHARD PAZDUR

Division of Oncology Drug Products, Center for Drug Evaluation and Research,
U.S. Food and Drug Administration, Rockville, Maryland, USA

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Key Words. Vorinostat • Histone deacetylase inhibitor • HDAC • Cutaneous T-cell lymphoma • CTCL

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.

LEARNING OBJECTIVES
After completing this course, the reader will be able to:
1. Add vorinostat to the armamentarium of drugs for CTCL.
2. Identify the mechanism of action of vorinostat.
3. Identify goals of therapy of CTCL.
4. Identify active CTCL therapies.
5. Identify CTCL response criteria.
CME Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com

ABSTRACT
On October 6, 2006, the U.S. Food and Drug Adminis-
tration granted regular approval to vorinostat
(Zolinza威; Merck & Co., Inc., Whitehouse Station, NJ),
a histone deacetylase inhibitor, for the treatment of cu-
taneous manifestations of cutaneous T-cell lymphoma
(CTCL) in patients with progressive, persistent, or re-
current disease on or following two systemic therapies.
The pivotal study supporting approval was a single-arm
open-label phase II trial that enrolled 74 patients with
stage IB and higher CTCL who had failed two systemic
therapies (one of which must have contained bexaro-
tene). Patients received vorinostat at a dose of 400 mg
orally once daily, which could be reduced for toxicity to
300 mg daily or 300 mg 5 days a week. The median age of
patients was 61 years. Sixty-one patients (82%) had
stage IIB or higher CTCL and 30 patients (41%) had
Sézary syndrome. The median duration of protocol
treatment was 118 days. The primary efficacy endpoint
was objective response assessed by the Severity-
Weighted Assessment Tool. The objective response rate
was 30% (95% confidence interval [CI], 19.7%–
41.5%), the estimated median response duration was
168 days, and the median time to tumor progression was
202 days. An additional single-center study enrolled 33
patients with similar baseline and demographic features
as the pivotal trial. Thirteen of the 33 received vorino-
stat (400 mg/day). The response rate in these 13 patients
was 31% (95% CI, 9.1%– 61.4%). The most common
clinical adverse events (AEs) of any grade were diarrhea
(52%), fatigue (52%), nausea (41%), and anorexia

Correspondence: Bhupinder S. Mann, M.D., U.S. Food and Drug Administration, White Oak Campus, 10903 New Hampshire Avenue,
Building 22, Room 2103, Silver Spring, Maryland 20993-0002, USA. Telephone: 301-796-1411; Fax: 301-796-9845; e-mail:
bhupinder.mann@fda.hhs.gov Received December 6, 2006; accepted for publication July 24, 2007. ©AlphaMed Press 1083-7159/2007/
$30.00/0 doi: 10.1634/theoncologist.12-10-1247

The Oncologist 2007;12:1247–1252 www.TheOncologist.com

1248
(24%). Grade 3 or 4 clinical AEs included fatigue (4%)
and pulmonary embolism (5%). Hematologic labora-
tory abnormalities included thrombocytopenia (26%)
and anemia (14%). Chemistry laboratory abnormali-
ties included increased creatinine (16%), increased se-
rum glucose (69%), and proteinuria (51%). Most
abnormalities were National Cancer Institute Common
INTRODUCTION
Epigenetic changes in gene expression may play an impor-
tant role in cancer growth. The opposing activities of his-
tone acyltransferases (HATs) and histone deacetylases
(HDACs) regulate gene expression by altering chromatin
structure. HATs, by acylating histones, produce an open
chromatin structure, resulting in greater accessibility of
regulatory proteins to DNA. HDACs, by contrast, catalyze
acyl group removal, leading to a closed chromosomal con-
figuration and transcriptional repression [1, 2]. HDAC in-
hibition may permit re-expression of proteins that promote
apoptosis and cell differentiation while inhibiting cell cy-
cling and cell division [3].
Vorinostat (suberoylanilide hydroxamic acid, Zolinza威;
Merck & Co., Inc., Whitehouse Station, NJ) is an orally ac-
tive, potent inhibitor of HDAC activity whose structure is
shown in Figure 1. Vorinostat inhibits HDAC by binding to
a zinc ion in the catalytic domain of the enzyme [4]. Vori-
nostat demonstrated activity in murine xenograft models
and it was additive or synergistic when combined with che-
motherapy drugs in induction of differentiation and apopto-
sis of various cancer cell lines [5].
Phase I vorinostat clinical trials were initiated with both
an i.v. and an oral drug formulation [2, 6, 7]. The oral for-
mulation was developed for ease in daily administration
and is the approved formulation of the drug. At steady state
in the fed-state, oral administration of multiple 400-mg
doses of vorinostat resulted in a mean area under the con-
centration–time curve and maximum concentration and a
median maximum time of 6.0 ⫾ 2.0 ␮M䡠hour, 1.2 ⫾ 0.53
␮M, and 4 (0.5–14) hours, respectively.
Both the i.v. and oral vorinostat formulations were reason-
ably well tolerated. Dose-limiting toxicity included myelosup-
pression, gastrointestinal toxicity, and fatigue. Responses
were noted in both solid tumors and hematologic malignan-
cies, including one patient with heavily pretreated cutaneous
T-cell lymphoma (CTCL), who had stable disease.
Vorinostat and other HDAC inhibitors have demon-
strated activity in CTCL. Zhang and colleagues [8] investi-
gated the effect of vorinostat in CTCL cell lines and freshly
isolated peripheral blood lymphocytes (PBLs) from 11 pa-
Vorinostat in Advanced CTCL
Terminology Criteria for Adverse Events grade 1 or 2.
Grade 3 or greater chemistry abnormalities included
hyperglycemia, hypertriglyceridemia, and hyperurice-
mia, hypoglycemia, hypokalemia, hyponatremia, hy-
perkalemia, hypercholesterolemia, hypophosphatemia,
and increased creatinine. The Oncologist 2007;12:
1247–1252
tients with circulating malignant T cells. Vorinostat treat-
ment (1.0 –5.0 ␮M for 48 hours) induced dose-dependent
apoptosis in all three CTCL cell lines and also induced apop-
tosis up to 59% in 10 of 11 CTCL PBLs.
While vorinostat evaluation was being conducted in a
variety of tumors, a cyclic tetrapeptide HDAC inhibitor,
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depsipeptide, was being evaluated primarily in hematologic
malignancies. Using a human T-cell lymphoma cell line,
Piekarz et al. [9] demonstrated substantial apoptosis with-
out significant cell cycle arrest.
A phase I depsipeptide study reported partial responses
(PRs) in three of three study patients with CTCL and a com-
plete response (CR) in one patient with peripheral T-cell
lymphoma, unspecified [10]. A phase II depsipeptide study
reported objective responses in five of 19 assessable CTCL
patients, including two patients who achieved CRs [11].
A similar phase II trial of vorinostat (400 mg/day) en-
rolled 13 advanced, refractory CTCL patients who had re-
ceived a mean of five prior therapies (range, 1–19). Five
patients (38%) experienced a PR, with a mean duration of
response of 15 weeks. More than 50% of the study patients
reported clinically significant decreases in pruritus [12].
These CTCL results led the sponsor (Merck & Co. Inc.,
Whitehouse Station, NJ) to conduct and submit a single-arm
trial evaluating vorinostat efficacy, safety, and tolerability in
the treatment of CTCL patients who had failed two prior sys-
temic therapies for consideration of regulatory approval [13].
PATIENTS AND METHODS
Two phase II single-arm trials were submitted in support of
the efficacy of vorinostat and an additional 10 other phase I
and II clinical studies were reviewed to evaluate the safety
of vorinostat. The pivotal trial was an open-label, single-
Figure 1. Structure of vorinostat (suberoylanilide hydrox-
amic acid, SAHA).
Mann, Johnson, Cohen et al.
arm, multicenter study. The supportive trial was an open-
label, three-arm, nonrandomized, single-center study
conducted prior to the pivotal trial. Details of these trials
have recently been published [12, 13].
Eligible CTCL patients were ⱖ18 years old, with an
Eastern Cooperative Oncology Group performance status
score of 0 –2, life expectancy ⬎3 months, and stage IB or
higher disease [7]. Patients had to have progressive, persis-
tent, or recurrent disease following two systemic therapies,
one of which must have contained bexarotene (unless the
patient was intolerant to or not a candidate for bexarotene as
described in the bexarotene package insert). Persistent dis-
ease was defined by a lack of at least a 50% improvement on
therapy for at least 3 months unless the patient was intoler-
ant to therapy because of the toxicities. Use of topical or
systemic corticosteroids was not allowed on study except in
Sézary syndrome patients who were on systemic steroids
for at least 3 months, in patients on a stable daily dose
equivalent to ⱕ10 mg of prednisone for at least 4 weeks im-
mediately prior to receiving study therapy, or in patients
who had been on topical steroids for at least 3 months on a
dose that did not exceed 0.1% triamcinolone acetonide
cream or equivalent for at least 4 weeks immediately prior
to receiving study therapy.
The starting dose of vorinostat was 400 mg once daily,
preferably taken with food. Two dose reductions were al-
lowed for toxicity: 300 mg once daily or 300 mg once daily
for 5 consecutive days per week, if necessary. Treatment
was continued until progressive disease, unacceptable tox-
icity, lack of efficacy, or a patient’s withdrawal of consent.
The primary study objective was the objective response
rate. Secondary objectives were time to objective response,
response duration, time to progression, pruritis relief, and
safety and tolerability of vorinostat. Skin disease was as-
sessed and scored at baseline and at scheduled follow-up
visits using the Severity-Weighted Assessment Tool
(SWAT). Abnormal skin not elevated from the normal skin
was defined as patch, abnormal skin elevated from the nor-
mal skin by ⬍5 mm was defined as plaque, and a plaque
elevated ⱖ5 mm was considered as tumor. Percentages of the
total body surface area involved with patch, plaque, and tumor
were severity-weighted by multiplying by factors of 1, 2, and
4, respectively, and summed to give an overall SWAT score.
A clinical complete response (CCR) required a 100%
improvement with no evidence of the disease and a PR re-
quired at least a 50% decrease in SWAT score compared
with baseline, with confirmation by a second assessment af-
ter at least 4 weeks. Patients who achieved a CCR or PR by
SWAT had a full computed tomography assessment of their
nodal disease after the response was confirmed by a second
assessment. Progressive disease (PD) required at least a
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1249
25% increase in SWAT score compared with baseline in re-
sponding patients, a 50% increase in SWAT score com-
pared with the nadir, or at least a 50% increase in the sum of
the products of the greatest diameters of pathologically pos-
itive lymph nodes (documented by biopsy) compared with
baseline. PD required confirmation by a second assessment
1– 4 weeks later whenever possible. Stable disease (SD) did
not meet the criteria for either response or progression. Fol-
low-up study evaluations were performed at weeks 2, 4, 6,
and 8, and every 4 weeks thereafter until the patient was dis-
continued from the study. For each study patient, global
half-body photographs and close-up photographs of distinct
individual lesions were taken serially to document changes
in the skin disease. These photographs were supportive
only and were not used to derive SWAT scores.
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The intensity of pruritus was evaluated using a patient-
completed questionnaire at baseline and at each follow-up
visit. A 10-point scale was used and skin itch over the past
week was assessed: 0 ⫽ no itching and 10 ⫽ itching as bad
as it can be. A baseline pruritus score of ⱖ3 was required
for assessment. A three-point decrease in pruritis intensity,
without an increase in the use of antipruritic medications
and confirmed by a second assessment at least 4 weeks
later, was considered clinically significant.
The safety and tolerability of vorinostat were assessed
in the two submitted phase II CTCL trials and in 10 other
trials that included vorinostat treatment in patients with
other solid tumors and hematologic malignancies. Adverse
events were graded using the National Cancer Institute Com-
mon Terminology Criteria for Adverse Events, Version 3.0.
RESULTS
The larger phase II trial, conducted by 18 centers in the U.S.
and Canada, enrolled 74 patients who had stage IB or higher
advanced CTCL. Patient and disease characteristics are
shown in Table 1. Previous CTCL therapies included:
bexarotene, 71 (96%); interferon, 47 (64%); photopheresis,
27 (37%); methotrexate, 26 (35%); denileukin diftitox, 23
(31%); glucocorticoids, 18 (24%); doxorubicin, 13 (18%);
gemcitabine, 12 (16%); cyclophosphamide, 9 (12%); and
chlorambucil, 7 (10%).
Objective response rates (all treated patients) are shown
in Table 2. The median times to response were 55 and 56
days, respectively, in the overall and stage IIB or higher dis-
ease patients. All responses except one were partial. In all
analyzed subsets, the response rate was about 30%. The
observed response rate in patients with IIB or higher stage
disease was 30% (95% confidence interval [CI], 18.5%–
42.6%). Patients who had failed bexarotene had a response
rate of 31% (5 of 16), similar to the rate (29%, 2 of 7) ob-
served in patients who had earlier responded to bexarotene.
1250 Vorinostat in Advanced CTCL

Table 1. Patient and disease characteristics at baseline Table 2. Objective response rates to vorinostat
(n ⫽ 74) Responders
Characteristic Value Patient population n (%) 95% CI
Age (years) All patients 74 22 (30%) 19.7–41.5
Median (range) 60 (39–83) Stage IIB or higher 61 18 (30%) 18.5–42.6
Gender, n (%) Patients with Sézary 30 10 (33%) 17.3–52.8
Male 38 (51%) syndrome
Female 36 (49%) Patients with T3 22 5 (23%) 7.8–45.4
tumor disease
CTCL stage, n (%)
Abbreviation: CI, confidence interval.
IB 11 (15%)
IIA 2 (3%)
IIB 19 (26%)
III 22 (30%) endpoint, objective response, was measured by the seven-
IVA 16 (21%) point Physician’s Global Assessment scale. The median

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IVB 4 (5%) age was 67.0 years (range, 26.0 – 82.0). Fifty-five percent of
Racial origin, n (%) patients were male. Eighty-five percent of patients had
Asian 1 (1.4%) stage IIB, III, IVA, or IVB disease. The median number of
Black 11 (15%)
prior systemic therapies was four (range, 0 –11). Response
rates (all partial) were 30.8%, 9.1%, and 33.3% in cohorts 1,
Other 1 (1.4%)
2 and 3, respectively. The overall objective response rates
White 61 (83%)
were 24.2% (8 of 33) and 25% (7 of 28) in patients with
Time from initial CTCL diagnosis 2.6 (0–27)
(years), median (range) stage IIB or higher disease and 36.4% (4 of 11) in patients
Number of prior systemic treatments, 3 (1–12) with Sézary syndrome. The 300-mg twice-daily regimen
median (range) had higher toxicity with no additional clinical benefit over
BSA involvement (%), median (range) the 400-mg once-daily regimen. The median time to re-
Patch 16% (0–100) sponse was 83.5 days (range, 25–153 days). The median re-
Plaque 6% (0–98) sponse duration was 106 days (range, 66 –136 days). The
Tumor 0% (0–92) median time to progression was 211.5 days (range, 94 –255
SWAT score days).
Mean (SD) 82 (70) Although pruritis relief was a secondary endpoint of the
Median (range) 75 (1.5–366) large phase II trial, the absence of both a control arm and of
Pruritis score blinding led the U.S. Food and Drug Administration (FDA)
Mean (SD) 6 (2.5) reviewers to consider the results as unreliable. Pruritis data
Median (range) 6 (0–10)
were not included in the label.

Abbreviations: BSA, body surface area; CTCL, cutaneous

T-cell lymphoma; SD, standard deviation; SWAT,
Severity-Weighted Assessment Tool.
The median response duration (based on a 50% increase in
SWAT score from the nadir) was estimated to be 168 days.
The median time to tumor progression was estimated as 202
days.
The smaller phase II study included 33 CTCL patients
who were refractory or intolerant to at least one treatment.
Patients were assigned to one of three cohorts: cohort 1, 400
mg once daily (13 patients); cohort 2, 300 mg twice daily 3
days/week (11 patients); or cohort 3, 300 mg twice daily for
14 days followed by a 7-day rest (induction) followed by
200 mg twice daily (nine patients). The primary efficacy
SAFETY
Safety data from 86 CTCL patients who received vorinostat
(400 mg daily) in the two submitted phase II trials are sum-
marized in Table 3. Other submitted trials included vorino-
stat doses and schedules different from the recommended
dose and schedule for CTCL or included patients with dis-
eases other than CTCL.
The median number of days on protocol treatment was
97.5 (range, 2– 480⫹ days). Seventeen (19.8%) patients re-
ceived treatment for ⬎24 weeks and eight (9.3%) patients
were treated beyond 1 year. Adverse events resulted in dis-
continuation of therapy in eight patients (9.3%). An addi-
tional nine patients (10.5%) required a dose reduction.
Table 3 summarizes clinical or laboratory adverse
events, regardless of causality, occurring in ⱖ10% of pa-
Mann, Johnson, Cohen et al. 1251

ureteric obstruction. Whereas cardiac toxicity was ex-

Table 3. Clinical adverse events reported by ⱖ10% of pected, based on preclinical data, myocardial damage was
patients
not detected.
Vorinostat, 400 mg once daily
(n ⴝ 86)
Adverse event All grades Grades 3–4
DISCUSSION
CTCL is an uncommon, chronic, debilitating, heteroge-
n % n % neous disease. Early-stage patients (i.e., those with limited
Fatigue 45 52.3 3 3.5 patches and plaques) achieve reasonable results with skin-
Diarrhea 45 52.3 0 0.0 directed therapies such as topical agents, total skin electron
Nausea 35 40.7 3 3.5 beam radiation, and psoralen photochemotherapy. For the
Dysgeusia 24 27.9 0 0.0 more advanced stages of disease, where tumors and/or eryth-
Thrombocytopenia 22 25.6 5 5.8 roderma are present, systemic therapies are usually required
Anorexia 21 24.4 2 2.3 [14]. Goals of therapy are improved cosmesis, reduction in tu-
Weight decrease 18 20.9 1 1.2 mor burden, decreased tumor ulceration and secondary infec-
Muscle spasms 17 19.8 2 2.3 tion, and relief of symptoms of pain and pruritis [15].

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Alopecia 16 18.6 0 0.0 Prolongation of survival is obviously an important goal, but
Dry mouth 14 16.3 0 0.0 one difficult to access because of the rarity and chronic nature
Blood creatinine 14 16.3 0 0.0
of disease and because most patients receive many treatment
increase regimens during the course of their illness.
Chills 14 16.3 1 1.2 The observed response rates and response durations ob-
Vomiting 13 15.1 1 1.2 served with vorinostat appear comparable with those ob-
Constipation 13 15.1 0 0.0 tained with the other FDA-approved CTCL therapies,
Dizziness 13 15.1 1 1.2 bexarotene (Targretin威; Ligand Pharmaceuticals, San Di-
Anemia 12 14.0 2 2.3 ego, CA) and denileukin diftitox, although response assess-
Decreased appetite 12 14.0 1 1.2 ment in the vorinostat and denileukin diftitox trials was
Peripheral edema 11 12.8 0 0.0
based on the SWAT whereas assessment in the bexarotene
trials was by the Composite Assessment of Index Lesion
Headache 10 11.6 0 0.0
Disease Severity tool. Bexarotene, at a dose of 300 mg/m2
Pruritus 10 11.6 1 1.2
per day orally, produced an overall response rate of 32.3%
Cough 9 10.5 0 0.0
(one complete tumor response and 19 partial tumor re-
Upper respiratory 9 10.5 0 0.0
infection sponses) [16, 17] and denileukin diftitox, at a dose of 9 or 18
Pyrexia 9 10.5 1 1.2 ␮g/kg per day, had an overall tumor response rate of 30%
(seven complete tumor responses and 14 partial tumor re-
sponses) in 71 treated patients [18].
The observed 30% objective response rate of skin dis-
tients. Thrombocytopenia and anemia were the most com- ease (evaluated using SWAT, supported by patient photo-
mon hematologic toxicities. Other laboratory abnormalities graphs) with a median response duration of 168 days in a
reported included increased serum glucose in 69% of CTCL heavily pretreated advanced CTCL patient population was
patients (59 of 86), transient increases in serum creatinine felt by the FDA reviewers to represent clinical benefit.
in 46.5% of patients (40 of 86), and proteinuria in 51.4% of Vorinostat was thus granted regular approval on October 6,
patients (38 of 74). 2006. The approved indication is that vorinostat is indicated
Serious adverse events occurring in this patient popula- for treatment of cutaneous manifestations of CTCL in pa-
tion included pulmonary embolism, reported in four pa- tients with progressive, persistent, or recurrent disease on or
tients (4.7%); squamous cell carcinoma, three patients following two systemic therapies. The recommended vori-
(3.5%); and anemia, two patients (2.3%). There were single nostat dose is 400 mg orally once daily with food.
events of cholecystitis, death (of unknown cause), deep
vein thrombosis, enterococcal infection, exfoliative derma-
titis, gastrointestinal hemorrhage, infection, lobar pneumo- ACKNOWLEDGMENTS
nia, myocardial infarction, ischemic stroke, pelviureteric The views expressed are the result of independent work and
obstruction, sepsis, spinal cord injury, streptococcal bacte- do not necessarily represent the views and findings of the
remia, syncope, T-cell lymphoma, thrombocytopenia, and U.S. Food and Drug Administration.

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1252
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 FDA Approval Summary: Vorinostat for Treatment of Advanced Primary
Cutaneous T-Cell Lymphoma
Bhupinder S. Mann, John R. Johnson, Martin H. Cohen, Robert Justice and Richard
Pazdur
Oncologist 2007;12;1247-1252
DOI: 10.1634/theoncologist.12-10-1247
This information is current as of April 9, 2009

Updated Information including high-resolution figures, can be found at:

& Services http://www.TheOncologist.com/cgi/content/full/12/10/1247

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