Dual blockade of the EGFR and COX-2 pathways: a phase II trial of cetuximab and celecoxib in patients with chemotherapy refractory metastatic colorectal cancer.

Abstract

OBJECTIVES:

The epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) pathways play key and often complementary roles in the pathogenesis of colorectal cancer (CRC). This study explores the clinical and biological effects of combined blockade of these pathways.

METHODS:

Cetuximab-naive patients with refractory CRC were treated with cetuximab (400 mg/m loading dose followed by weekly cetuximab at 250 mg/m) and celecoxib (200 mg orally twice daily). Urinary PGE-M, a stable metabolite of PGE2 that correlates with in vivo COX-2 activity, and serum TGF-α, a ligand that binds to EGFR, were measured serially to assess the biological effect of COX-2 and EGFR blockade.

RESULTS:

Seventeen patients accrued in this study. Of the 13 patients evaluable for response, 2 (15.4%) had confirmed partial responses, 4 (30.8%) had stable disease, and 7 (53.8%) had progressive disease. The median progression-free survival for all evaluable patients was 55 days (95% confidence interval, 45-112; range, 10-295 d). This study was terminated early owing to lack of sufficient clinical activity. There were no statistically significant differences in serum TGF-α or urinary PGE-M between cycles in responders or nonresponders.

CONCLUSIONS:

This regimen resulted in response rates similar to those published for cetuximab monotherapy in patients with recurrent CRC. Apart from a higher than expected rate of infusion reactions, no other unexpected toxicities were observed. No differences in serum TGF-α or urinary PGE-M between cycles were seen, suggesting that the appropriate targets may not have been hit.

• Authors: Emily Chan, Bonnie Lafleur, Mace L Rothenberg, Nipun Merchant, Albert Craig Lockhart, Bakula Trivedi, Christine H Chung, Robert J Coffey, Jordan D Berlin
• Journal: American journal of clinical oncology (Am J Clin Oncol) Vol. 34 Issue 6 Pg. 581-6 (Dec 2011) ISSN: 1537-453X [Electronic] United States
• PMID: 21217396 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Pyrazoles
• Sulfonamides
• Cyclooxygenase 2
• EGFR protein, human
• ErbB Receptors
• Celecoxib
• Cetuximab

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage, adverse effects, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Celecoxib
• Cetuximab
• Colorectal Neoplasms (drug therapy, pathology)
• Cyclooxygenase 2 (metabolism)
• Disease-Free Survival
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Female
• Humans
• Male
• Mice
• Mice, Nude
• Neoplasm Metastasis
• Neoplasm Staging
• Pyrazoles (administration & dosage, adverse effects, therapeutic use)
• Signal Transduction (drug effects)
• Sulfonamides (administration & dosage, adverse effects, therapeutic use)
• Xenograft Model Antitumor Assays