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Reckamp, K.L. et al.

Reckamp, Krysan, Morrow, Milne, Newman, Tucker, Elashoff, Dubinett, Figlin,

A phase I trial to determine the optimal biological dose of celecoxib when combined with erlotinib in advanced non-small cell lung cancer.

PURPOSE: Overexpression of cyclooxygenase-2 ( COX-2) activates extracellular signal-regulated kinase/mitogen-activated protein kinase signaling in an epidermal growth factor receptor (EGFR) tyrosine kinase inhibition (TKI)-resistant manner. Because preclinical data indicated that tumor COX-2 expression caused resistance to EGFR TKI, a phase I trial to establish the optimal biological dose (OBD), defined as the maximal decrease in urinary prostaglandin E-M (PGE-M), and toxicity profile of the combination of celecoxib and erlotinib in advanced non-small cell lung cancer was done. EXPERIMENTAL DESIGN: Twenty-two subjects with stage IIIB and/or IV non-small cell lung cancer received increasing doses of celecoxib from 200 to 800 mg twice daily (bid) and a fixed dose of erlotinib. Primary end points included evaluation of toxicity and determination of the OBD of celecoxib when combined with erlotinib. Secondary end points investigate exploratory biological markers and clinical response. RESULTS: Twenty-two subjects were enrolled, and 21 were evaluable for the determination of the OBD, toxicity, and response. Rash and skin-related effects were the most commonly reported toxicities and occurred in 86%. There were no dose-limiting toxicities and no cardiovascular toxicities related to study treatment. All subjects were evaluated on intent to treat. Seven patients showed partial responses (33%), and five patients developed stable disease (24%). Responses were seen in patients both with and without EGFR-activating mutations. A significant decline in urinary PGE-M was shown after 8 weeks of treatment, with an OBD of celecoxib of 600 mg bid. CONCLUSIONS: This study defines the OBD of celecoxib when combined with a fixed dose of EGFR TKI. These results show objective responses with an acceptable toxicity profile. Future trials using COX-2 inhibition strategies should use the OBD of celecoxib at 600 mg bid.[1]

References

A phase I trial to determine the optimal biological dose of celecoxib when combined with erlotinib in advanced non-small cell lung cancer. Reckamp, K.L., Krysan, K., Morrow, J.D., Milne, G.L., Newman, R.A., Tucker, C., Elashoff, R.M., Dubinett, S.M., Figlin, R.A. Clin. Cancer Res. (2006) [Pubmed]

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