Phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin

We conducted a phase I and pharmacokinetic study of the topoisomerase II ca talytic inhibitor fostriecin. Fostriecin was administered intravenously ove r 60 min on days 1-5 at 4-week intervals. Dose was escalated from 2 mg m(-2 ) day(-1) to 20 mg m(-2) day(-1) in 20 patients. Drug pharmacokinetics was analysed with high performance liquid chromatography with UV-detection, Pla sma collected during drug administration was tested in vitro for growth inh ibition of a teniposide-resistant small-cell lung cancer (SCLC) cell line. The predominant toxicities were elevated river transaminases (maximum commo n toxicity criteria (CTC) grade 4) and serum creatinine (maximum CTC grade 2). These showed only a limited increase with increasing doses, often recov ered during drug administration and were fully reversible. Duration of elev ated alanine-amino transferase (ALT) was dose-limiting in one patient at 20 mg m(-2), Other frequent toxicities were grade 1-2 nausea/vomiting, fever and mild fatigue. Mean fostriecin plasma half-life was 0.36 h (initial; 95% CI, 0-0.76 h) and 1.51 h (terminal; 95% GI, 0.41-2.61. hf. A metabolite, m ost probably dephosphorylated fostriecin, was detected in plasma and urine. No tumour responses were observed, but the plasma concentrations reached i n the patients were insufficient to induce significant growth inhibition in vitro. The maximum tolerated dose (MTD) has not been reached, because drug supply was stopped at the 20 mg m-2 dose level. However, further escalatio n seems possible and is warranted to achieve potentially effective drug lev els. Fostriecin has a short plasma half-life and longer duration of infusio n should be considered.