NEW YORKClinical trials of the experimental oral agent
exisulind (Prevatac) are underway for chemopre-vention of a variety
of cancers, according to a report at Current Concepts in Cancer
Therapy II, a scientific symposium sponsored by Long Ridge Associates.
A metabolite of sulindac, a nonsteroidal anti-inflammatory drug,
exisulind selectively induces apoptosis in neoplastic cells, said
Rifat Pamukcu, MD, chief scientific officer and senior vice president
for research and development at Cell Pathways, Inc., Horsham,
Pennsylvania. [See the box for an explanation of the drugs
mechanism of action.]
SAANDS: How They Work
Both exisulind and CP461, a more potent compound now entering
SAANDs inhibit a cyclic GMP phosphodiesterase, uncovered in the
By selectively blocking that enzyme, SAANDs allow the apoptotic
The FDA has designated exisulind an orphan drug meriting
fast-track development for aden-omatous polyposis coli (APC),
Dr. Pamukcu said, and its first trials were in patients with this
hereditary disease, which is also known as familial adenomatous
Exisulind is now being tested in other precancerous lesions and in
recurrence prevention in some cancers. Treatment of frank cancers is
also being explored, but most research to date has been directed
toward chemoprevention. For every one person with cancer,
Dr. Pamukcu observed, there are 10 people with a precancerous lesion.
The initial trial in 18 patients with APC who retained their rectum
after colectomy was designed to determine the maximum tolerated
dosage. The optimal dose turned out to be 600 mg daily.
The highest daily dose tested, 800 mg, induced active
regression of the existing polyps, Dr. Pamukcu reported,
but after 3 to 5 weeks, about half the patients showed
very-low-grade liver enzyme elevations. These reversed completely
when dosage was dropped to 600 mg, where good regression of polyps is
In 16 patients, polyps of 6 mm or less regressed, and larger polyps
remained stable. No increase in cell apoptosis was seen in normal
The first patient enrolled, an 18-year-old woman with more than 100
polyps in her rectum had been told that if she did not respond
to the drug, she would lose her rectum within a year, Dr.
Pamukcu said. After 6 months at the lowest dose tested, 400 mg daily,
her polyps began disappearing. At 45 months, she is the patient
longest on exisulind and still has her rectum.
The subsequent international double-blind, placebo-controlled phase
III trial enrolled 73 APC patients with subtotal colectomies. It
was a prevention trial so all polyps were aggressively removed at
baseline, Dr. Pamukcu said, and then any new polyps that
formed were removed at 6 and at 12 months.
The results showed a greater than 50% reduction in new polyp
formation, compared with placebo, among the 34 eligible patients who
completed the 12-month study (P < .05). Eligible patients were
those who formed approximately 10 to 40 polyps per year.
Based on these findings, Cell Pathways plans to submit a New Drug
Application for exisulind to the FDA later this summer. In light of
the relatively low percentage of patients who met inclusion criteria
in this study, the company will also assemble additional clinical
data from other ongoing APC trials of exisulind, to be added to the
NDA later this year.
Prostate Cancer Study
Interim data from a double-blind placebo-controlled trial of
exisulind in 96 postsurgical prostate cancer patients suggest it may
be effective in preventing recurrences, Dr. Pamukcu said. Limited to
patients with radical prostatectomies whose PSA levels had been
rising for at least 4 months, the trial is to run for a year, with
patients receiving 250 mg of the drug daily.
The early data show a flattening of the PSA rises after 2 to 3
months, he said. Because the patients do not have
prostates, he added, they have no source of PSA other
than their microscopic metastases. Other prostate cancer trials
are planned with exisulind, Dr. Pamukcu said, particularly in
Already underway are a trial aimed at preventing breast cancer
recurrences in patients in remission after treatment for a
recurrence; a phase II trial in Barretts esophagus; and a phase
IB/II trial in lung cancer. Dr. Pamukcu also noted that animal
studies have shown a significant impact of exisulind on bladder