WASHINGTON--Despite questions about dose levels and number of
treatment courses, the FDAs Oncology Drugs Advisory Committee
(ODAC) gave a vote of confidence to Seragens Ontak (denileukin
diftitox or DAB389IL-2) for its approval for use in
cutaneous T-cell lymphoma (CTCL) that persists or recurs despite
prior therapy. Ontak is an interleukin-2 (IL-2) fusion protein that
delivers a diphtheria toxin fragment to lesions via IL-2 receptor
binding. The panel was not asked to formally recommend the agent to
CTCL (mycosis fungoides) is an uncommon disease, with only 800 cases
diagnosed each year in the United States. The disease begins as
plaques on the skin and spreads to blood and organs, producing
itching, susceptibility to infection, and disfigurement.
The skin of a patient with CTCL presents a poor barrier to staph
infections, said Timothy Kuzel, MD, of Northwestern University.
"Patients are culture dishes waiting to get into trouble,"
At present, most CTCL treatments are topical, and all topical agents
are toxic to the skin over time. "Standard therapies produce a
high rate of sepsis," said Paul A. Bunn, Jr., MD, of the
University of Colorado, speaking on behalf of Seragen.
"This is a disease that is almost biblical in its
disfigurement," said the National Cancer Institutes Edward
A. Sausville, MD, a consultant to the FDA panel, "so symptomatic
relief is badly needed."
In a blinded, two-arm, parallel study of 71 patients stratified by
stage, Seragen reported a 30% overall response rate and a 10%
complete response rate with use of Ontak. Two-thirds of patients
showed improvement in disease burden.
In all, 456 patients have received Ontak, Dr. Kuzel said, speaking
for Seragen, and all had at last one side effect: infections, fever,
chills, asthenia, and others. Typically, these were worse in the
first or second cycles, he said, and some may be prevented with
steroids, which were banned from the trial because of their potential
Drug infusion reactions were seen in 68% of patients, and 10% had
vascular leak syndrome. Since DAB389IL-2
incorporates a modified diphtheria toxin, the drug may cross react
with diphtheria antibodies, but this did not predict any increased
side effects, according to Seragen.
Dr. Sausville noted that entry criteria included IL-2 receptor
status, but this was not mentioned in the proposed labeling. Jean
Nichols, PhD, of Seragen, responded that IL-2 receptor status had to
be positive for the drug to exert its cytotoxic effects, but that the
assay used to measure IL-2 receptor status may not be sufficiently
sensitive to identify all
IL-2 receptor-positive patients. Given that information, another
reviewer suggested opening up the next trial to IL-2
receptor-negative patients as well.
As for dosage, Seragen said that early trials had indicated that 27
µg/kg/day was the maximum tolerated dose, so trial doses were
set at 9 and 18 µg/kg/d. Dr. Sausville noted that the 18
µg/kg/d dose showed better efficacy in stage T3 patients, but
not in T1 or T2 patients.
Trial results were almost flat after the first three courses, raising
questions about efficacy beyond that point. "The value of
treatment beyond three courses is not visible, likely due to antibody
production," Dr. Sausville said. "But more courses of Ontak
may be appropriate in some cases."
Some reviewers suggested starting with the lower dosage to reduce
toxicity, but, Dr. Sausville said, "You have to get as much drug
as possible as quickly as possible to the receptor, rather than limit
the number of cycles." The next trials, he said, should look at
which T-stage responds to which dose. "Higher concentrations
will likely penetrate much better into the tumor mass."