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FDA Okays Zolinza for CTCL Skin Lesions

FDA Okays Zolinza for CTCL Skin Lesions

ROCKVILLE, Maryland--The
Food and Drug Administration has approved
Zolinza (vorinostat, Merck) as a
once-a-day oral treatment of the skin
manifestations of cutaneous T-cell lymphoma
(CTCL) in patients whose disease
has persisted, progressed, or recurred
during or following two systemic therapies.
The agency granted Zolinza marketing
approval as part of its Orphan
Drug program and on the basis of data
from two open-label clinical studies in
patients with refractory CTCL. Treated
patients had an objective response rate of
nearly 30%.

The drug is taken daily with food as a
single 400 mg oral dose. If the patient is
intolerant to therapy, the dose may be
reduced to 300 mg orally once daily with
food. The dose may be further reduced
to 300 mg once daily with food for 5
consecutive days each week.

Zolinza is the first of a new class of
drugs, the histone deacetylase (HDAC)
inhibitors, to gain FDA approval. Based
on in vitro studies, Zolinza inhibits the
enzymatic activity of HDAC1, HDAC2,
HDAC3, and HDAC6 at nanomolar concentrations. In some cancer cells, excess
amounts of HDAC prevent the activation
of genes that control normal cell
activity. Zolinza is believed to decrease
HDAC activity, which allows for the activation
of genes that may help to slow or
stop the growth of cancer cells. In a press
release, Merck noted that the exact
mechanism of the anticancer effect of
Zolinza has not been fully characterized.

Pivotal Study
Merck submitted as its pivotal study
an open-label, single-arm, nonrandomized,
multicenter trial of 74 patients
treated with 400 mg Zolinza once daily.
The primary endpoint was the response
rate of the skin disease. Secondary endpoints
were response duration, time to
progression, and time to objective response.
Patients had received a median of three therapies prior to enrollment
(range, 1 to 12).

Of the 74 patients, 22 (29.7%) had an
objective response to Zolinza, as did 18
(29.5%) of the 61 patients with stage IIB
or higher CTCL. Median times to response,
respectively, were 55 and 56 days
(range, 28 to 171 days). Median duration
was not reached because most responses
continued at the time of analysis, but it
was estimated to exceed 6 months in both
the overall population and patients with
stage IIB or higher disease. When end of
response was defined as a 50% increase
in a scale that assesses skin lesions, the
estimated median response duration was
168 days and the median time to tumor
progression was 202 days.

Dosing Study
In the open-label, nonrandomized
dosing study, 33 patients were divided
into three cohorts receiving one of three
Zolinza doses: 400 mg daily, 300 mg twice
daily 3 days per week, or 300 mg twice
daily for 14 days followed by a 7-day rest.
Overall, 8 (24.2%) of the patients had an objective response and 7 (25%) of the 28
with stage IIB or higher disease responded.
The overall response rates were
30.8%, 9.1%, and 33.3% in Cohorts 1, 2,
and 3, respectively. The 300 mg twice
daily regimen had higher toxicity with
no additional clinical benefit over the
400 mg once daily regimen.

Among the 8 responders, median time
to response was 83.5 days (range, 25 to
153 days); duration of response lasted a
median of 106 days (range, 66 to 136
days); and median time to progression
was 211.5 days (range, 94 to 255 days).

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