Clinical and pharmacologic phase I study of Cemadotin-HCl* (LU103793), a novel antimitotic peptide, given as 24-hour infusion in patients with advanced cancer

Purpose. To determine the maximum tolerable dose (MTD), principal toxicity, and pharmacologic behaviour of Cemadotin-HCl, a novel antimitotic peptide. Patients and methods. Cemadotin-HCl (10.0 to 27.5 mg/m(2)/day every three w eeks) was administered as a 24-hour intravenous (i.v.) continuous infusion to patients with advanced cancer. Pharmacokinetic analyses were performed d uring the first treatment cycle. Blood samples were taken over 48 hours and analyzed by radioimmunoassay. Results. Hypertension was the dose-limiting toxicity (DLT). This type of to xicity was observed at all dose levels: but grade 3 (CTC) was observed only at dose levels 20.0, 25.0 and 27.5 mg/m(2). This effect was reversible but in three patients associated with signs of cardiac ischemia. Other signifi cant toxic effects were neutropenia, asthenia, tumor pain and transient liv er enzyme elevation. A linear pharmacokinetics was observed. The best curve fit was obtained with a two-compartment model with a terminal half-life of approximate to 10 hours at each dose level, a volume of distribution at st eady state of approximate to 9 l/m(2) and a total clearance of approximate to 0.6 l/hour/m(2). Neither partial nor complete responses were observed al though minor tumor regressions were seen in a patient with carcinoma of unk nown primary (CUP) and in another patient with liver metastases from a colo n cancer. Conclusions. Hypertension was the dose-limiting toxicity of Cemadotin-HCl a dministered as a continuous 24-hour infusion. The recommended dose for furt her evaluation of its anticancer efficacy in disease-oriented phase II stud ies with this schedule is 15.0 mg/m(2). The nature of the principal cardio- vascular toxicity remains unclear. The observed toxicities appeared to be s ignificant but manageable.