Clinical phase I and pharmacokinetic study of S 16020, a new olivacine derivative: report on three infusion schedules

S 16020, a new 9-OH olivacine derivative, is a novel topoisomerase II inhibitor with activity in cell lines presenting the classical multidrug resistance phenotype. This report summarizes, in addition to pharmacokinetic data, the whole phase I clinical experience of S 16020 using three different infusion schedules. Asthenia and skin toxicity were the main side effects. In an attempt to understand the skin toxicity mechanism, experiments in animals were performed, the results of which are reported. S 16020 showed rapid tumor necrotizing activity in some patients, with soft tissue metastases of epidermoid tumors and pain at the tumor site. To document the side effects of S 16020 and tumor site reactions (pain, edema, inflammatory signs), inflammatory parameters and some cytokines were measured. In our patients there was no hemolysis and no detection of anti-S 16020 antibodies, confirming the absence of immunogenicity of the compound. Based on the overall data of the three infusion schedules of S 16020, the dose of 100 mg/m(2) over 3 h every 3 weeks was selected for phase II studies.