BETHESDA, MdG.D. Searle & Co. has won FDA approval for its
COX-2 inhibitor Celebrex (celecoxib) as an oral adjunct to usual care
(endoscopic surveillance and surgery) to reduce the number of
adenomatous colorectal polyps in patients with familial adenomatous
polyposis (FAP). The FDA initially approved Celebrex for treating
osteoarthritis and rheumatoid arthritis in April 1998.
The approval came quickly after the recommendation from the Oncologic
Drugs Advisory Committee (ODAC) that the FDA grant accelerated
approval for the new indication.
FAP is a rare, inherited conditionabout 1 in 10,000
birthsin which the affected person develops hundreds to
thousands of intestinal polyps, many of which become cancerous unless
Adenomas appear by about 10 years of age in 15% of people with
FAP, and by 30 years of age in 90%, Bernard Levin, MD, vice
president for cancer prevention, M.D. Anderson Cancer Center, said at
the ODAC meeting. At the time of symptomatic diagnosis, at an
average age of 36 years, 70% of these individuals have colorectal
malignancy, and over the lifetime of this illness, there is a 100%
cancer risk, typically in the fourth and fifth decades. No true
pharmacologic treatment is available for these patients.
Celebrex inhibits cyclooxygenase-2 (COX-2), an enzyme whose
overex-pression has been linked to inflammation, FAP, and the
development of colon and rectal tumors . COX-2 is expressed in
all stages of human colon carcinogenesis, said Jaime L.
Masferrer, PhD, Searles COX-2 cancer project leader.
At the ODAC meeting, Searle presented data from a single, randomized,
double-blind, placebo-controlled study of 83 FAP patients conducted
at M.D. Anderson and St. Marks Hospital, London, England.
Two of the enrollees dropped out of the study for reasons unrelated
to toxicity; 29 had colorectal polyps, 46 had both colorectal and
duodenal polyps, and 6 had duodenal involvement only. Each had a
minimum of five polyps of at least 2 mm in size.
Patients received a placebo, 100 mg Celebrex twice daily, or 400 mg
Celebrex twice daily. Researchers performed endoscopic evaluations
when patients entered the study and after 6 months of treatment. The
primary efficacy endpoint was a mean percent of change in the
colorectal polyp count in specific areas marked by tattoos.
In its analysis, the FDA review team accepted 78 patients and agreed
completely with the company in its interpretation of the mean percent
of polyp decrease. Both found a 4.5% reduction in the number of
polyps in the placebo arm; a 14.5% reduction in the 100 mg Celebrex
twice daily group; and a 28.0% reduction in the 400 mg Celebrex twice
In a review of rectal photos from 28 patients, the sponsor reported
an 11% reduction in the placebo group and a 2.2% reduction in the 100
mg Celebrex twice daily arm, while the FDA found a 15% and an 85.3%
increase in the two, respectively. In the 400 mg Celebrex twice daily
group, the sponsor reported a 33.3% decrease in mean percent of
polyps, and the FDA put the decrease at 32.6%.
Our conclusion is that celecoxib 400 mg twice daily results in
focal reduction and regression of colorectal polyps, said
Ernest T. Hawk, MD, of the NCIs Division of Cancer Prevention,
which helped fund the study. Globally, there is improvement in
the endoscopic appearance of both the colorectum and duodenum.
Safety data for all 83 patients originally enrolled in the study
showed that 65% of the placebo group and 47% of the patients in each
of the Celebrex arms suffered grade 2 adverse events, largely
gastrointestinal problems (35%, 29%, and 34%, respectively). Six
percent of the placebo arm, 9% of the 100 mg twice daily arm, and 6%
of the 400 mg twice daily arm suffered grade 3 events.
For any adverse eventheadache, dyspepsia, upper
respiratory tract infection, diarrhea, sinusitis, abdominal pain, and
nauseathere is no evidence of any dose response, Gary B.
Gordon, MD, PhD, Searles director of cancer prevention/treatment
clinical research, told the advisory panel.
ODAC members clearly have concerns about any FDA approval that would
indicate a drug prevents cancer. For example, in recommending in 1998
that the FDA approve Nolvadex (tamoxifen) for use in healthy women at
high risk of breast cancer, the committee specifically rejected using
the word prevention and suggested instead its approval for use in
reducing a risk of breast cancer.
At one point, the company was asked whether it claimed that Celebrex
reduced cancer in FAP patients. We are only claiming the
reduction and regression of polyps in FAP patients; were making
no claims about cancer or its outcome, stressed Searle
co-president Philip Needleman, PhD.
Committee members pondered whether reducing the polyp burden would
delay or even alleviate the need for surgery in FAP patients, and
whether this might alter lifetime survival.
Proposed Phase IV Study
The committee also addressed the phase IV study required by the
accelerated approval process. Dr. Gordon said that Searle was
putting on the table a proposed study for FDA
consideration. It would be double-blind and controlled, and would
enroll 322 cancer-free individuals between the ages of 12 and 19 who
had been genetically diagnosed with FAP. They would be randomized
equally to either 100 mg twice daily or 400 mg twice daily of
Celebrex. The study endpoint would be the number of patients who
developed cancer or had surgery to remove polyps before age 21.
However, ODAC members fired a series of probing questions about the
value and protocol of the proposed study. Why include the 100 mg
dose, if the 400 mg dose is clearly superior, as the
study presented to the committee indicated? Why, in a postmarketing
study, would the company focus on teenagers instead of on patients
similar to the group initially studied? Should the study focus more
on the upper GI tract?
Finally, given the study results presented to ODAC and the fact that
Celebrex is an approved drug, will so many physicians begin treating
FAP patients with the drug that it will be impossible to carry out a
meaningful study? The window has closed, I suspect, said
Derek Raghavan, MD, PhD, head of medical oncology, University of
Searle officials said they would consult with FDA staff to work out
an acceptable phase IV study.