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 a dose on a protracted, continuous daily schedule, to characterize its pharmacokinetic behavior, and to acquire preliminary evidence of anticancer activity. Patients and Methods: Patients with advanced solid malignancies were treated with escalating doses of OSI-774 in three study parts (A to C) to evaluate progressively longer treatment intervals. Part A patients received OSI-774 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 once 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 characterized. 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. Uninterrupted, daily administration of OSI-774 150 mg/d represented the MTD on a protracted daily schedule. The pharmacokinetics of OSI-774 were dose independent; repetitive daily treatment did not result in drug accumulation (at 150 mg/d [average]: minimum steady-state plasma concentration, 1.20 ± 0.62 μg/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 plasma concentration-time curve for OSI-420 relative to OSI-774, 0.12 ± 0.12 μg/h/mL). Conclusion: The recommended dose for disease-directed studies of OSI-774 administered orally on a daily, continuous, uninterrupted schedule is 150 mg/d. OSI-774 was well tolerated, and several patients with epidermoid malignancies demonstrated either antitumor activity or relatively long periods of stable disease. The precise contribution of OSI-774 to these effects is not known.