A phase I clinical and pharmacokinetic study of the dolastatin analogue cemadotin administered as a 5-day continuous intravenous infusion

Purpose: The dolastatins are a class of naturally occurring cytotoxic pepti des which function by inhibiting microtubule assembly and tubulin polymeriz ation. Cemadotin is a synthetic analogue of dolastatin 15 with potent antip roliferative and preclinical antitumor activity. This report describes a ph ase I study to evaluate the administration of cemadotin to adult cancer pat ients by a 5-day continuous intravenous (CIV) infusion. Methods: All patien ts had histologically confirmed refractory solid tumors. The dose was escal ated from an initial level of 2.5 mg/m(2) (0.5 mg/m(2) daily) according to a modified Fibonacci algorithm. A minimum of three patients was evaluated a t each dose level until the maximum tolerated dose (MTD) was established. T reatment was repeated every 21 days until patients were removed from the st udy due to toxicity or disease progression. Drug-related toxicities were ev aluated and graded by the U.S. National Cancer Institute's Common Toxicity Criteria. A radioimmunoassay (RIA) that detected both the parent drug and i ts metabolites with an intact N-terminal region of the molecule was used fo r pharmacokinetic studies. Results. Twenty heavily pretreated patients rece ived a total of 40 courses of cemadotin over five dose levels ranging from 2.5 to 17.5 mg/m(2). Reversible dose-related neutropenia was the principal dose-limiting toxicity and 12.5 mg/m(2) was established as the MTD. Nonhema tologic toxicities attributed to the drug were moderate, and there was no e vidence of the cardiovascular toxicity noted in the prior phase I studies o f cemadotin given IV as a 5-min injection or 24-h infusion. There were no o bjective antitumor responses. rime courses of the cemadotin RIA equivalent concentration in whole blood were defined in 14 patients during the first c ycle of therapy. The RIA-detectable species exhibited apparent first-order pharmacokinetics across the entire range,of doses. The mean +/- SD of the o bserved steady-state blood concentration at the 12.5 mg/m(2) MTD was: 282 /- 7 nM (n = 3). Blood levels decayed monoexponentially following the end o f the infusion, with a mean half-life of 13.2 +/- 4.3 h (n = 14) in all pat ients. Mean values (n = 14) of the total blood clearance and apparent volum e of distribution at steady state were 0.52 +/- 0.09 l/h/m(2) and 9.9 +/- 3 .3 l/m(2), respectively. Conclusions: The cardiotoxic effects of cemadotin were completely avoided by administering it as a 120-h CIV infusion. Thus, cardiovascular toxicity appears to be associated with the magnitude of the peak blood levels of the parent drug or its metabolites, whereas myelotoxic ity is related to the duration of time that blood levels exceed a threshold concentration. Nevertheless, the data acquired during the extensive clinic al experience with cemadotin requires careful examination to assess whether advancing this compound into disease-oriented efficacy studies is merited.