Biomarker-Based Phase I Dose-Escalation, Pharmacokinetic, and Pharmacodynamic Study of Oral Apricoxib in Combination With Erlotinib in Advanced Nonsmall Cell Lung Cancer

BACKGROUND: Apricoxib, a novel once-daily selective cyclooxygenase-2 inhibitor, was investigated in combination with erlotinib for recurrent stage IIIB/IV nonsmall cell lung cancer to determine the maximum tolerated dose, dose-limiting toxicity, and recommended phase II dose (RP2D) based on changes in urinary prostaglandin E(2) metabolite (PGE-M). METHODS: Patients received escalating doses of apricoxib (100, 200, and 400 mg/day) in combination with erlotinib 150 mg/day until disease progression or unacceptable toxicity. Urinary PGE-M was used to assess biologic activity and inform the optimal biologic dose. RESULTS: Twenty patients were treated (3 at 100 mg; 3 at 200 mg; 14 at 400 mg apricoxib) with a median of 4 cycles (range, 2-14 cycles); 8 patients (40%) received prior EGFR-directed therapies. No dose-limiting toxicity was observed. Study drug-related adverse events (AEs) included diarrhea, rash, dry skin, anemia, fatigue, and increased serum creatinine; 4 patients had grade >= 3 drug-related AEs (diarrhea, perforated duodenal ulcer, hypophosphatemia, and deep vein thrombosis). The RP2D was 400 mg/day based on safety, biologic activity based on decreases in urinary PGE-M, and pharmacokinetics. One patient had a partial response, and 11 had stable disease. Stable disease was observed in patients who had received prior EGFR inhibitor therapy but was greater in patients not previously treated with an EGFR inhibitor. Seventeen patients had elevated urinary PGE-M at baseline, and 14 (70%) had a decrease from baseline, which was associated with disease control. CONCLUSIONS: Apricoxib plus erlotinib was well tolerated and yielded a 60% disease control rate. A phase II trial is currently investigating 400 mg/day apricoxib plus 150 mg/day erlotinib in patients selected based on change in urinary PGE-M. Cancer 2011;117:809-18. (C) 2070 American Cancer Society