Once-Daily Celecoxib Effective for Preventing Sporadic Colorectal Adenomas Slideset on: Arber N, Rácz I, Spicak J, et al. Chemoprevention of colorectal adenomas with celecoxib in an international randomized, placebo-controlled, double-blind trial. Program and abstracts of the 97th Annual Meeting of the American Association for Cancer Research; April 1-5, 2006; Washington, DC. Abstract CP-4.

clinicaloptions.com/onco Highlights of AACR Arber N, et al Annual AACR Meeting. Abstract CP-4. Background  Cyclooxygenase-2 (COX-2) implicated in development of colorectal cancer  COX-2 inhibitors reduce incidence of precursor colorectal adenomas in animal models and in humans with hereditary adenomatous polyposis  Current study assessed efficacy of celecoxib COX-2 inhibitor for preventing colorectal adenomas –International, randomized, placebo-controlled, double-blind trial –107 centers in 32 countries

clinicaloptions.com/onco Highlights of AACR Arber N, et al Annual AACR Meeting. Abstract CP-4. Study Design Patients with colorectal adenomas ≥ 6 mm in diameter or with multiple adenomas (N = 1561)* Celecoxib 400 mg/day (n = 933) Placebo (n = 628) 3:2 Randomization Stratification by low-dose aspirin use Year 1 Colonoscopy Year 3 Colonoscopy *Randomization preceded by 30-day placebo lead-in phase.

clinicaloptions.com/onco Highlights of AACR Arber N, et al Annual AACR Meeting. Abstract CP-4. Eligibility  Inclusion criteria –≥ 30 years of age –Colonoscopy within 3 months of enrollment, removal of 1 adenoma ≥ 6 mm or ≥ 2 adenomas < 10 mm  Exclusion criteria –Familial adenomatous polyposis or hereditary nonpolyposis –Inflammatory bowel disease –NSAID, COX-2 inhibitor, or sulfonamide hypersensitivity –History of gastric ulceration, large bowel resection

clinicaloptions.com/onco Highlights of AACR Arber N, et al Annual AACR Meeting. Abstract CP-4. Baseline Characteristics  Baseline characteristics well balanced between treatment groups Characteristic Celecoxib (n = 933) Placebo (n = 628) Median age, yrs61 Male, %6765 Body mass index, kg/m 2 27 Parent with colorectal cancer, %1517 Use of low-dose aspirin, %17 Adenoma ≥ 1 cm, %4847 Mean number of adenomas1.9 Prior cardiovascular events, %1411

clinicaloptions.com/onco Highlights of AACR Arber N, et al Annual AACR Meeting. Abstract CP-4. Main Findings  89% of patients had Year 1 colonoscopy; 79% had Year 3 colonoscopy  Celecoxib significantly reduced incidence of ≥ 1 adenoma on follow-up colonoscopy through Year 3 –Results comparable for aspirin users and nonusers Patient Group Relative Risk of Adenoma Detection Through Year 3 P Value All patients0.64<.0001  Aspirin users  Aspirin nonusers0.65<.0001

clinicaloptions.com/onco Highlights of AACR Arber N, et al Annual AACR Meeting. Abstract CP-4. Main Findings (cont’d)  Celecoxib significantly reduced incidence of ≥ 1 adenoma on follow-up colonoscopy through Year 3 for high-risk patients (ie, ≥ 3 adenomas at baseline, ≥ 60 years, or parent with colorectal cancer) –Results not significant for aspirin users; likely due to small sample size Patient Group Relative Risk of Adenoma Detection Through Year 3 P Value High-risk patients  Aspirin users  Aspirin nonusers

clinicaloptions.com/onco Highlights of AACR Arber N, et al Annual AACR Meeting. Abstract CP-4. Main Findings (cont’d)  Significantly more renal/hypertensive and cardiovascular adverse events observed among celecoxib patients, especially nonaspirin users Adverse Event Placebo, % (n = 628) Celecoxib, % (n = 933) P Value All adverse events NS Renal/hypertensive <.01 Gastrointestinal NS Cardiovascular4.87.5<.05 Serious adverse events NS  Hazard ratio for cardiovascular event on celecoxib: 1.3 (95% CI: ) –Patients with history of cardiovascular events: 1.6 (95% CI: )

clinicaloptions.com/onco Highlights of AACR Arber N, et al Annual AACR Meeting. Abstract CP-4. Summary of Key Conclusions  Celecoxib effective for prevention of colorectal adenomas –Reduced 3-year adenoma detection rate by –36% for all patients –33% for patients at high-risk for developing adenomas  Celecoxib associated with significant increase in renal/hypertensive and cardiovascular events –Safety of once-daily dosing relative to twice-daily dosing warrants future study