Abel G

Ashley SE

Cairnduff F

Calvert AH

Evans BD

Graham MA

Gumbrell LA

Judson IR

Rutty CJ

Wilman DEV

Trimelamol is an analogue of hexamethylmelamine and pentamethylmelamine 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 109/liter. Thrombocytopenia and anemia also occurred but were not dose limiting. Doses &gt;1500 mg/m2 caused WHO grade 3 nausea and vomiting 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 109/liter. Nonhematological toxicities were also less marked on the fractionated schedule. Antitumor effects were observed including 1 complete and 9 partial responses. Demonstration of activity in ovarian cancer has led to further evaluation in this disease using the 3-day schedule at a dose of 800 mg/m2 daily for 3 days. </sup

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Phase-I trial and pharmacokinetics of trimelamol (N2,N4,N6- trihydroxymethyl-N2,N4,N6-trimethylmelamine)

Phase-I trial and pharmacokinetics of trimelamol (N<sup>2</sup>,N<sup>4</sup>,N<sup>6</sup>- trihydroxymethyl-N<sup>2</sup>,N<sup>4</sup>,N<sup>6</sup>-trimethylmelamine)

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