Phase I study of gefitinib plus celecoxib in patients with metastatic and/or locally recurrent squamous cell carcinoma of the head and neck (SCCHN)

Abstract

5540 Background: Treatment options for incurable metastatic and/or locally recurrent SCCHN are limited. Platinum-based therapy yields response rates of approximately 30%, and median survival of 6–7 months. Epidermal growth factor receptor (EGFR) and Cyclooxygenase-2 (COX-2) are both overexpressed and thought to contribute to the malignant phenotype in SCCHN. The EGFR inhibitor, gefitinib, has a single-agent response rate of 11% in this population. Preclinical and pharmacodynamic data suggest that the addition of a COX-2 inhibitor may enhance the antitumor effect of gefitinib. Methods: A phase I trial was designed to determine the maximum tolerated doses (MTD) of gefitinib and celecoxib (GC) in patients with incurable SCCHN. Secondary objectives were to describe toxicities of this combination and to study biomarkers of activity, including Ki-67, CD31, activation of EGFR, ERK1/2, and Akt, and serum IL-8 and EGFR. Response will also be determined. MTD was defined as one dose level below which dose-limiting toxicities (DLTs) occurred in 2 or more of 6 patients, or the highest dose level tested. Eligible patients had measurable metastatic and/or locally recurrent SCCHN, at least 1 prior chemotherapy, performance status 2 or better, and adequate end-organ function. Results: Thus far, 12 patients have enrolled. Dose escalation and toxicities are outlined in Table 1. The most common toxicities were rash (predominately acneiform), diarrhea and hand-foot syndrome (HFS). To date, no DLTs have occurred. Three of nine evaluable patients achieved a partial response. Additional transient responses were observed. Biomarker analysis is pending. Conclusions: Overall, GC is very well-tolerated in patients with incurable SCCHN. Preliminary data suggest that celecoxib enhances gefitinib activity. A phase II study is warranted. No significant financial relationships to disclose.