PHASE-I AND PHARMACOKINETIC STUDY OF THE WATER-SOLUBLE DOLASTATIN-15 ANALOG LU103793 IN PATIENTS WITH ADVANCED SOLID MALIGNANCIES

Purpose: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic profile of the dolastatin 15 an alog LU103793 when administered daily for 5 days every 3 weeks. Patien ts and Methods: Fifty-six courses of LU103793 at doses of 0.5 to 3.0 m g/m(2) were administered to 26 patients with advanced solid malignanci es. Pharmacokinetic studies were performed on days 1 and 5 of course o ne. Pharmacokinetic variables were related to the principal toxicities . Results: Neutropenia, peripheral edema, and liver function rest abno rmalities were dose-limiting at doses greater than 2.5 mg/m(2) per day . Four of six patients developed DLT at 3.0 mg/m(2) per day, whereas t wo of 12 patients treated at 2.5 mg/m(2) per day developed DLT, Pharma cokinetic parameters were independent of dose and similar on days 1 an d 5. Volume of distribution at steady-state (V-ss) was 7.6 +/- 2.0 L/m (2), clearance 0.49 +/- 0.18 L/h/m(2), and elimination half-life (t(1/ 2)) 12.3 +/- 3.8 hours. Peak concentrations (C-max) on day 1 related t o mean percentage decrement in neutrophils (sigmoid maximum effect (E- max) model). Patients who experienced dose-limiting neutropenia had si gnificantly higher C-max values than patients who did not, whereas non hematologic DLTs were more related to dose. Conclusion: The recommende d dose for phase II evaluations of LU103793 daily for 5 days every 3 w eeks is 2.5 mg/m(2) per day. The lack of prohibitive cardiovascular ef fects and the generally acceptable toxicity profile support the ration ale for performing disease-directed evaluations of LU103793 on the sch edule evaluated in this study J Clin Oncol 16:2770-2779. (C) 1998 by A merican Society of Clinical Oncology.