Phase II study of the clinical and biological activity of cetuximab and celecoxib in patients (pts) with refractory colorectal cancer (CRC)

Abstract

14516 Background: The epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) pathways play key roles in colon carcinogenesis. EGFR and COX-2 signaling can be mutually reinforcing. Celecoxib, a selective COX-2 inhibitor, inhibits the EGFR pathway through inhibition of PI3/Akt and NF-κB pathways. This study explores the clinical and biological effects of blockade of complementary pathways of the EGFR by combining cetuximab with celecoxib. Methods: Cetuximab-naive pts with refractory CRC were treated with cetuximab (400 mg/m2 loading dose followed by weekly cetuximab at 250 mg/m2) and celecoxib (200 mg orally twice daily). Patients were assessed for response every 8 weeks. Urinary PGE-M, a metabolite of PGE-2 which correlates with in vivo COX-2 activity, and serum TGF-a, a ligand that binds to EGFR, were measured to assess the biological effect of COX-2 and EGFR blockade. Results: Seventeen of a planned 40 pts accrued to this study. Currently, data is available on 12 of these patients. Three pts had to stop treatment on 1st infusion due to a grade 3 cetuximab infusion reaction. One pt had a mild infusion reaction and was successfully rechallenged after pre-medication and a slower infusion rate. By RECIST criteria, 1 pt (8.3%) achieved a partial response (PR) and 4 pts (33%) had a best response of stable disease (SD). The mean time on study for the 9 pts without grade 3 infusion reaction was 95.7 days (range 28- 175). Pts with SD or PR were on study for a mean of 135 days (range 107–175 days) and pts with progressive disease (PD) were on study for a mean of 47 days (range 28–56 days). Baseline urinary PGE-M levels in pts with SD or PR were higher than in pts with PD (30.5+17.6 vs 18.1+9.4 ng/mg Cr). Baseline serum TGF-a levels were similar between the two groups (27.1+9.6 vs 25.4+10.3 pg/ml respectively). Conclusions: In preliminary analysis, this regimen resulted in response rates similar to published response rates for single agent cetuximab. Pts with at least SD had higher baseline urinary PGE-M levels, which may serve as a marker for efficacy of this combined therapy. Data on serial TGF-a and PGE-M levels will be presented. Response data on all 17 pts will be presented. Supported by P50 CA95103 and Bristol-Myers Squibb. Celecoxib provided by Pfizer. [Table: see text]