Phase I trial and pharmacokinetics of @entity28058 ( XXXX ).

@entity43 @entity137 @entity390 @entity417 @entity882 @entity72759 @entity391 @entity28058 @entity11558
@entity28058 is an analogue of @entity11558 and @entity72759 which does not require metabolic activation and is sufficiently soluble to allow parenteral administration. A Phase I trial has been performed at the Royal Marsden Hospital in which two schedules of administration have been evaluated, a single i.v. infusion repeated every 3 weeks and 3 daily doses repeated every 3 weeks. Pharmacokinetic analysis was performed at all dose levels on both schedules and a linear correlation was demonstrated between dose and area under the curve. Myelosuppression was dose limiting for single dose administration with a maximum tolerated dose of 2400 mg/m2. Median leukocyte nadirs at 1800, 2100, and 2400 mg/m2 were 3.2, 2.6, and 1.5 x 10(9)/liter. @entity882 and @entity417 also occurred but were not dose limiting. Doses greater than 1500 mg/m2 caused WHO grade 3 @entity390 and @entity391 but no acute sedation. Three day administration appeared to be less myelosuppressive, giving a maximum tolerated dose of 1000 mg/m2. Median leukocyte nadirs at 800, 900, and 1000 mg/m2 daily for 3 days were 3.0, 2.3, and 1.5 x 10(9)/liter. Nonhematological @entity137 were also less marked on the fractionated schedule. Antitumor effects were observed including 1 complete and 9 partial responses. Demonstration of activity in @entity43 has led to further evaluation in this disease using the 3-day schedule at a dose of 800 mg/m2 daily for 3 days.
