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

Abstract

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/m2/day every three weeks) was administered as a 24-hour intravenous (i.v.) continuous infusion to patients with advanced cancer. Pharmacokinetic analyses were performed during 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 toxicity was observed at all dose levels, but grade 3 (CTC) was observed only at dose levels 20.0, 25.0 and 27.5 mg/m2. This effect was reversible but in three patients associated with signs of cardiac ischemia. Other significant toxic effects were neutropenia, asthenia, tumor pain and transient liver enzyme elevation. A linear pharmacokinetics was observed. The best curve fit was obtained with a two- compartment model with a terminal half-life of ≃10 hours at each dose level, a volume of distribution at steady state of ≃9 1/m2 and a total clearance of ≃ 0.6 1/hour/m2. Neither partial nor complete responses were observed although minor tumor regressions were seen in a patient with carcinoma of unknown primary (CUP and in another patient with liver metastases from colon cancer. Conclusions: Hypertension was the dose-limiting toxicity of Cemadotin-HCl administered as a continuous 24-hour infusion. The recommended dose for further evaluation of its anticancer efficacy in disease-oriented phase II studies with this schedule is 15.0 mg/m2. The nature of the principal cardiovascular toxicity remains unclear. The observed toxicities appeared to be significant but manageable.