BETHESDA, Md—G.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 condition—about 1 in 10,000 births—in which the affected person develops hundreds to thousands of intestinal polyps, many of which become cancerous unless surgically removed.
“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, Searle’s 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. Mark’s 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 daily arm
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(Drug information on celecoxib) 400 mg twice daily results in focal reduction and regression of colorectal polyps,” said Ernest T. Hawk, MD, of the NCI’s 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 event—headache, dyspepsia, upper respiratory tract infection, diarrhea, sinusitis, abdominal pain, and nausea—there is no evidence of any dose response,” Gary B. Gordon, MD, PhD, Searle’s 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; we’re 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 Southern California.
Searle officials said they would consult with FDA staff to work out an acceptable phase IV study.
