NIH Suspends Celebrex Trial, Orders Review of COX-2 Studies

March 2, 2003

This special “annual highlights” supplement to Oncology News International (ONI)is a compilation of selected news on important advances in the management ofgastrointestinal cancers over the past year, as reported in ONI. Guest Editor, Dr.James L. Abbruzzese, comments on the reports included herein and discussesdevelopments in the clinical management of GI cancers, with a look at the impactof targeted agents with cytotoxic chemotherapy, first-line and adjuvant therapies foradvanced disease, and the role of statins and COX-2 inhibitors in prevention.

BETHESDA, Maryland-Aftersuspending use by study participantsof the selective COX-2 inhibitor celecoxib(Celebrex, Pfizer) in the AdenomaPrevention With Celecoxib(APC) trial because of cardiovasculartoxicity, National Institutes of Health(NIH) director Elias A. Zerhouni, MD,ordered a review of all NIH-supportedstudies involving COX-2 inhibitors.The National Cancer Institute(NCI) alone has more than 40 ongoingCOX-2 prevention and clinical trialsin progress, including the APC."We are now informing all principalinvestigators for these studies andwill ask them to communicate directlywith their study participants and explainthe risks and benefits," Dr. Zerhounisaid. "Also, we are asking eachinvestigator to inform us of their plansto analyze their data in light of the newinformation. And we are asking institutionalreview boards for all relatedtrials to assess the new information,and to conduct a safety review as well."Increased CadiovascularEventsNIH suspended the administrationof celecoxib to APC participants onNCI's recommendation after thestudy's independent safety and monitoringboard found an increased riskof cardiovascular events in the trial ofmore than 2,000 people, which is aimedat assessing the drug's ability to preventadenomas. All study participantshad had adenomatous polyps removedand were randomized to three arms:either 200 mg or 400 mg of celecoxibtwice daily, or placebo. NIH and Foodand Drug Administration (FDA) officialsannounced suspending celecoxib'suse in APC during a telephonepress conference."Patients in the clinical trial taking400 mg of celecoxib twice daily had a3.4 times greater risk of cardiovascu lar events, compared to those takingplacebo," said FDA acting commissionerLester Crawford, DVM, PhD."For patients in the trial taking 200 mgof celecoxib twice daily, the risk was2.5 times greater. The average durationof treatment in the trial was 33months. A similar ongoing trial comparingcelecoxib 400 mg once a day vsplacebo in patients followed for a similarperiod of time has not shown anincreased risk."Participants in the APC trial will nolonger receive celecoxib, but they willremain under observation for the plannedlength of the study. The trial,which began in 2000, is scheduled toend in the spring of 2005Vioxx WithdrawalThe cardiovascular problems associatedwith celecoxib came to lightafter NCI director Andrew C. von Eschenbach,MD, ordered the additionof greater cardiovascular expertise tothe safety and monitoring boards overseeinginstitute-sponsored studies ofall drugs in the class. The order wasprompted by the withdrawal of theCOX-2 inhibitor rofecoxib (Vioxx,Merck) from the market in September2004. Merck voluntarily recalled rofecoxibafter researchers found that peoplewho took it for more than 18months in a study testing the drug'spower to prevent colon adenomas haddouble the risk of cardiovascular toxicitiesas the placebo arm. The NCIreview began with the APC trial.Dr. Crawford also noted that clinicalinvestigators have found thatpatients treaded with valdecoxib (Bextra,Pfizer) have an increased cardiovascularrisk after heart surgery. "Physiciansshould consider this evolvinginformation in considering the risksand benefits of Celebrex in individualpatients," Dr. Crawford said. "FDAadvises evaluating alternative therapy.At this time, if physicians determinethat continued use is appropriate forindividual patients, FDA advises thelowest dose of Celebrex."