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

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 LU103793 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 (Vss) was 7.6 +/- 2.0 L/m2, clearance 0.49 +/- 0.18 L/h/m2, and elimination half-life (t1/2) 12.3 +/- 3.8 hours. Peak concentrations (Cmax) on day 1 related to mean percentage decrement in neutrophils (sigmoid maximum effect (Emax) model). Patients who experienced dose-limiting neutropenia had significantly higher Cmax 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 LU103793 on the schedule evaluated in this study.

• Authors: M A Villalona-Calero, S D Baker, L Hammond, C Aylesworth, S G Eckhardt, M Kraynak, R Fram, S Fischkoff, R Velagapudi, D Toppmeyer, B Razvillas, K Jakimowicz, D D Von Hoff, E Rowinsky
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 16 Issue 8 Pg. 2770-9 (Aug 1998) ISSN: 0732-183X [Print] United States
• PMID: 9704730 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Oligopeptides
• cemadotin

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Female
• Humans
• Male
• Middle Aged
• Neoplasms (drug therapy)
• Oligopeptides (administration & dosage, adverse effects, pharmacokinetics)