Phase I clinical and pharmacokinetic trial of the podophyllotoxin derivative NK611 administered as intravenous short infusion

Background: NK611 is a novel podophyllotoxin derivative. Compared with etop oside, NK611 carries a dimethyl-amino group at the D-glucose moiety. The an titumor activity of NK611 showed to be equal or superior to etoposide in a variety of in vitro and in vivo tumor models. The aim of our present study was to determine the maximum tolerated dose and the dose-limiting toxicitie s of NK611 administered as intravenous infusion over 30 min every 28 days. Patients and methods: 45 patients (7 female, 38 male; median age 54 [range 37-73]) were enrolled. In a first stage, NK611 was administered without hem atopoietic growth factor support; in a second stage, G-CSF was used for fur ther dose escalation. Toxicities were assessed using WHO-criteria. Results: Initially, the dose was escalated from 60 mg/m(2) to 120 mg/m(2). In a second patient cohort, doses were further escalated with G-CSF support with doses ranging from 140 mg/m(2) to 250 mg/m(2). Dose-limiting toxiciti es were granulocytopenia and thrombocytopenia. Non-hematologic toxicities c onsisted of alopecia, mild nausea, and infection. Four partial responses we re observed: two at 200 mg/m(2) (pleural mesothelioma, response duration 7 months, and non-small cell lung cancer, response duration 13 months), and t wo at 250 mg/m(2) (hepatocellular carcinoma, response duration 7 months, an d non-small cell lung cancer, response duration 2 months). Pharmacokinetic analyses were performed in all patients. Using an open 3-compartment model, the terminal half-life (t(1/2 gamma)) was 14.7 +/- 3.7 h. The AUC at 250 m g/m(2) was determined to be 330 +/- 147 mu g/mlh, the plasma clearance of N K611 was 16.2 +/- 8.2 ml/min.m(2) and the V-ss was 16.8 +/- 3.3 l/m(2). Pro tein binding of NK611 was 98.7%. Conclusion: the recommended dose for clinical Phase II studies is 120 mg/m( 2) without G-CSF support and 200 mg/m(2) with G-CSF support.