Phase I and pharmacokinetic study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) using a single intravenous dose schedule

Purpose: To perform a phase I and pharmacokinetics study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) a new ribonucleotide reductase inhibitor using a single intravenous (2-h) schedule every 4 weeks. 3-AP was given at a starting dose of 5 mg/m(2) with escalation based on a modified Fibonacci scheme. Patients and methods: A total of 27 patients with advanced cancer were entered into the study. Doses of 3-AP ranged from 5 mg/m2 to 105 mg/m2. Blood and urine samples were collected and 3-AP was measured by HPLC. Results: A total of 46 courses were evaluable. One patient developed grade 4 thrombocytopenia at the lowest dose level, and one patient had grade 3 anemia. Two patients developed grade 3 coagulation abnormalities. The only other toxicities of more than grade 1 occurring in more than 10% of patients were fever and asthenia. No toxicities were observed at the highest dose level. Peak serum concentration of 3-AP increased linearly with dose. No tumor responses were observed in this heavily pretreated population, although eight patients had stabilization of their disease. Conclusions: Relevant tumor inhibitory concentrations were achieved without significant toxicity using doses up to 105 mg/m2 on this single intravenous dose schedule. Prolonged administration schedules and combinations with other cytotoxic agents, strategies predicted to have greater antitumor efficacy according to preclinical studies, are under investigation.