Phase I and pharmacokinetic study of the water-soluble dolastatin 15 analog LU103793 in patients with advanced solid malignancies

Miguel A. Villalona-Calero, Sharyn D. Baker, Lisa Hammond, Cheryl Aylesworth, S. Gail Eckhardt, M. Kraynak, Robert Fram, Steven Fischkoff, Raja Velagapudi, Deborah Toppmeyer, Betty Razvillas, Krystyna Jakimowicz, Daniel D. Von Hoff, Eric Rowinsky

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36 Scopus citations

Abstract

Purpose: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic profile of the dolastatin 15 analog LU103793 when administered daily for 5 days every 3 weeks. Patients and Methods: Fifty-six courses of LU 103793 at doses of 0.5 to 3.0 mg/m2 were administered to 26 patients with advanced solid malignancies. Pharmacokinetic studies were performed on days 1 and 5 of course one. Pharmacokinetic variables were related to the principal toxicities. Results: Neutropenia, peripheral edema, and liver function test abnormalities were dose-limiting at doses greater than 2.5 mg/m2 per day. Four of six patients developed DLT at 3.0 mg/m2 per day, whereas two of 12 patients treated at 2.5 mg/m2 per day developed DLT. Pharmacokinetic parameters were independent of dose and similar on days 1 and 5. Volume of distribution at steady-state (V($$)) was 7.6 ± 2.0 L/m2, clearance 0.49 ± 0.18 L/h/m2, and elimination half-life (t 1/4 ) 12.3 ± 3.8 hours. Peak concentrations (C,(max)) on day 1 related to mean percentage decrement in neutrophils (sigmoid maximum effect (E(max)) model). Patients who experienced dose-limiting neutropenia had significantly higher C(max) values than patients who did not, whereas nonhematologic DLTs were more related to dose. Conclusion: The recommended dose for phase II evaluations of LU103793 daily for 5 days every 3 weeks is 2.5 mg/m2 per day. The lack of prohibitive cardiovascular effects and the generally acceptable toxicity profile support the rationale for performing disease-directed evaluations of LU 103793 on the schedule evaluated in this study.

Original languageEnglish (US)
Pages (from-to)2770-2779
Number of pages10
JournalJournal of Clinical Oncology
Volume16
Issue number8
DOIs
StatePublished - Aug 1998
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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