Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies

Purpose: To assess the feasibility of administering OSI-774, to recommend c c dose on a protracted, continuous daily schedule, to characterize its phar macokinetic behavior, and to acquire preliminary evidence of anticancer act ivity, Patients and Methods: Patients with advanced solid malignancies were treate d with escalating doses of OSI-774 in three study parts (A to C) to evaluat e progressively longer treatment intervals. Part A patients received OSI-77 4 25 to 100 mg once daily, for 3 days each week, for 3 weeks every 4 weeks. Part B patients received OSI-774 doses ranging from 50 to 200 mg given onc e daily for 3 weeks every 4 weeks to establish the maximum tolerated dose ( MTD). In part C, patients received this MTD on a continuous, uninterrupted schedule. The pharmacokinetics of OSI-774 and its O-demethylated metabolite , OSI-420, were characterised. Results: Forty patients received a total of 123 28-day courses of OSI-774. No severe toxicities precluded dose escalation of OSI-774 from 25 to 100 mg /d in part A. In part B, the incidence of severe diarrhea and/or cutaneous toxicity was unacceptably high at OSI-774 doses exceeding 150 mg/d. Uninter rupted, daily administration of OSI-774 150 mg/d represented the MTD on a p rotracted daily schedule. The pharmacokinetics of OSI-774 were dose indepen dent: repetitive daily treatment did not result in drug accumulation (at 15 0 mg/d [average]: minimum steady-state plasma concentration, 1.20 +/- 0.62 mug/mL; clearance rate, 6.33 +/- 6.41 L/h; elimination half-life, 24.4 +/- 14.6 hours; volume of distribution, 136. 4 +/- 93.1 L; area under the plasm a concentration-time curve for OSI-420 relative to OSI-774, 0.12 +/- 0.12 m ug/h/mL). Conclusion: The recommended dose for disease-directed studies of OSI-774 ad ministered orally on a daily, continuous, uninterrupted schedule is 150 mg/ d. OSI-774 was well tolerated, and several patients with epidermoid maligna ncies demonstrated either antitumor activity or relatively long periods of stable disease. The precise contribution of OSI-774 to these effects is not known. (C) 2001 by American Society of Clinical Oncology.