Q: Why has NCI been using COX-2 inhibitors in clinical trials?

Numerous compounds are examined by the National Cancer Institute (NCI) for their potential to prevent or treat cancer. One class of compounds, cyclooxygenase (COX) inhibitors, is currently being tested in both prevention and treatment clinical trials. Epidemiologic studies have shown that people who regularly take non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen to treat conditions like arthritis, have lower rates of colorectal polyps, colorectal cancer, and death due to colorectal cancer. NSAIDs block cyclooxygenase enzymes, which are produced by the body when there is inflammation and are also produced by precancerous tissues. Inhibition of COX-2 may help treat and prevent cancer, while inhibition of COX-1 may induce certain medical problems, like stomach bleeding, that occur when NSAIDS are taken regularly for long periods of time.

Q: What is Celebrex and why has NCI used this drug in their trials?

Pharmaceutical companies have created NSAIDs that block only COX-2; one of them, celecoxib (CelebrexTM), manufactured by Pfizer, Inc., New York, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of both osteoarthritis and adult rheumatoid arthritis (diseases in which the joints are inflamed) in December 1998. Because over a decade of scientific work has suggested the potential of COX-2 inhibitors to prevent and treat cancer, the National Cancer Institute (NCI) has clinical trials under way to look at the efficacy and safety of these drugs.

Q: What specific trials has NCI been conducting with Celebrex?

NCI's Division of Cancer Prevention (DCP) began its studies with celecoxib with a trial in people with Familial Adenomatous Polyposis (FAP). Patients with FAP develop hundreds to thousands of precancerous polyps (adenomas) throughout the colon and rectum. Left untreated, nearly all FAP patients develop colorectal cancer by their 40s and 50s. The primary treatment for FAP is surgical removal of most or all of the colon and rectum with subsequent surveillance of any remaining colorectal segment. In an NCI-sponsored trial, celecoxib helped reduce the number of colon polyps in patients with FAP. The results of this study were published in the New England Journal of Medicine on June 29, 2000, and led to FDA-approval of celecoxib as an adjunctive drug (an accessory or auxiliary agent) that could be added to the standard of care in people with FAP.

As of October 2004, DCP sponsored 23 trials of varying sizes to test the potential of celecoxib to prevent cancer in a number of organ sites. These trials range in size from under 10 participants to more than 2,000 and aim to prevent bladder, breast, cervical, colorectal, esophageal, head and neck, skin, lung, oral, and prostate cancers, as well as multiple myeloma. The majority of these trials are in collaboration with Pfizer, Inc.

Additionally, to examine potential benefits of COX-2 inhibitors for the treatment of patients with cancer, NCI's Division of Cancer Treatment and Diagnosis (DCTD) is sponsoring approximately 20 trials of varying sizes with celecoxib. The majority of these studies are small phase I or II clinical trials in cancers such as pancreatic, breast, ovarian, non-small cell lung, and solid tumors. DCTD also is sponsoring two ongoing randomized phase III clinical trials: the first trial compares two chemotherapy agents, exemestane vs anastrozole, in postmenopausal women with estrogen receptor-positive primary breast cancer; the second trial compares several chemotherapy agents in node-negative breast cancer patients. Both phase III trials randomized women to either those taking celecoxib or not taking celecoxib, in addition to the agents mentioned above.

Q: What is the status of the APC (Adenoma Prevention with Celecoxib) Trial?

The National Cancer Institute suspended the use of COX-2 inhibitor celecoxib (Celebrex™; Pfizer) on December 17, 2004, for all participants in a large colorectal cancer prevention clinical trial, the Adenoma Prevention with Celecoxib (APC) trial, because analysis by an independent Data Safety Monitoring Board (DSMB) showed a 2.5-fold increased risk of major fatal and non-fatal cardiovascular events for participants taking the drug compared to those on a placebo. Safety monitoring of a similar study that was sponsored by Pfizer, called the PreSAP cancer trial, did not find an increased risk of cardiovascular events.

Additional cardiovascular expertise was added to the safety monitoring committees at the request of the steering committees for these trials after a September 2004 report that the COX-2 inhibitor rofecoxib (Vioxx™) caused a two-fold increased risk of cardiovascular toxicities in a trial to prevent adenomas. The APC trial is a study of more than 2,000 people who have had a precancerous growth (adenomatous polyp) removed. They were randomized to take either 200 mg of celecoxib twice a day, 400 mg of celecoxib twice a day, or a placebo for three years. The trial began in early 2000 and is scheduled to be completed by spring 2005.

Investigators at the 100 sites in the APC trial, located primarily in the United States, with a few additional sites in the United Kingdom, Australia, and Canada, have been instructed to immediately suspend study drug use for all participants on the trial, although the participants will remain under observation for the planned remainder of the study.

Q: What actions is NCI planning to take to notify patients on other COX-2 inhibitor clinical trials?

NCI will notify all of the principal investigators of it's sponsored trials involving COX-2 inhibitors. They will be instructed to notify their institutional review boards, data safety monitoring boards, and participants about this new information. NCI will also require that the informed consent for these trials be revised to reflect this new information and that individuals in the trials be re-consented (asked to sign new consent forms with updated information about risks and benefits of the trials).

Q: What COX-2 inhibitors have been used in NCI-sponsored trials and what is their current status:

On September 30, 2004, the COX-2 inhibitor rofecoxib was removed from the market after a two-fold increased risk of cardiovascular toxicities was identified in people taking the drug for 18 months within a trial to prevent colon adenomas. The sponsor of the 2,600 person trial, Merck & Co., Inc. (New Jersey), sent a letter to physicians announcing the removal of the drug and explaining the action. NCI's Division of Cancer Prevention had planned to undertake a lung cancer prevention trial using rofecoxib, but has abandoned that plan following the withdrawl of rofecoxib.

Q: What did Pfizer, the manufacturer of Celebrex do in reaction to the removal of Vioxx from the market?

On October 18, 2004, Pfizer, Inc. announced it will initiate a trial of celecoxib users that will last for two years. The study will examine inflammation and cardiovascular events in osteoarthritis patients at high risk for heart disease. It will be conducted at major universities and hospitals around the world and is expected to start early in 2005, enrolling 4,000 patients who have had a recent heart attack and who also have a history of osteoarthritis.

For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at at 1-800-4-CANCER (1-800-422-6237).

For more information about regulation of COX-2 inhibitors by the FDA, please visit the FDA Web site at http://www.fda.gov/cder/drug/default.htm

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