A phase I trial of ZD1839 (Z), capecitabine (Cp), and celecoxib (Cel): Preliminary results of an amended schedule

Abstract

3159 Background: Angiogenesis is essential for tumor growth and metastasis. Distinct pro-angiogenic pathways are targeted by Cel (a cyclooxygenase-2 inhibitor), Z (an epidermal growth factor receptor tyrosine kinase inhibitor that results in reduced vascular endothelial growth factor expression), and Cp (a prodrug of 5-fluorouracil (5FU) activated by thymidine phosphorylase, a tumor-associated pro-angiogenic molecule). This abstract reports the results of an amended treatment schedule based on preclinical data suggesting that antitumor effects are sequence dependent. In vitro synergistic effects were observed when ZD1839 was administered prior to 5FU, additive effects with concomitant administration, and antagonistic effects when administered after 5FU. Methods: This phase I trial assesses the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetic interactions, and biologic effects of the combination of Z (250–500 mg/day days 1–14), Cp (1000 mg/m2- 2000 mg/m2/day days 8–21), and Cel (400 mg twice daily days 1–28) given in 28-day cycles. Results: Eleven patients (pts) have been enrolled and completed 29 treatment courses (crs). Median age was 66 (range 52–77) and median performance status was 1 (range 0–1). Dose-limiting toxicity (DLT) occurred in 1of 6 pts treated with ZD1839 250mg, Cp 1500mg/m2, and Cel 400mg and 1 of 1 pt treated with ZD1839 250mg, Cp 2000mg/m2, and Cel 400mg. DLT consisted of Gr 3–4 diarrhea and Gr 3 fatigue Additional Gr 3 toxicities considered to be possibly related to treatment include Gr3 hand-and-foot syndrome (HFS) in 2 courses. Grade 1–2 toxicities include fatigue (10 crs), acneiform rash (9 crs), diarrhea (8 crs), HFS (7 crs), and mucositis (5 crs). Three patients maintained stable disease for ≥ 5 cycles (adenocarcinoma unknown primary, gallbladder, and rectal cancer). Conclusions: Accrual is ongoing to determine the MTD. Tumor biopsies will then be obtained to assess effects on tumor metabolism and gene expression. No significant financial relationships to disclose.