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

Abstract

BACKGROUND:

NK611 is a novel podophyllotoxin derivative. Compared with etoposide, NK611 carries a dimethylamino group at the D-glucose moiety. The antitumor 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 toxicities 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 hematopoietic growth factor support; in a second stage, G-CSF was used for further dose escalation. Toxicities were assessed using WHO-criteria.

RESULTS:

Initially, the dose was escalated from 60 mg/m2 to 120 mg/m2. In a second patient cohort, doses were further escalated with G-CSF support with doses ranging from 140 mg/m2 to 250 mg/m2. Dose-limiting toxicities were granulocytopenia and thrombocytopenia. Non-hematologic toxicities consisted of alopecia, mild nausea, and infection. Four partial responses were observed: two at 200 mg/m2 (pleural mesothelioma, response duration 7 months, and non-small cell lung cancer, response duration 13 months), and two at 250 mg/m2 (hepatocellular carcinoma, response duration 7 months, and 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 (t1/2gamma) was 14.7 +/- 3.7 h. The AUC at 250 mg/m2 was determined to be 330 +/- 147 microg/mlh, the plasma clearance of NK611 was 16.2 +/- 8.2 ml/min x m2 and the V(ss) was 16.8 +/- 3.3 l/m2. Protein binding of NK611 was 98.7%.

CONCLUSION:

the recommended dose for clinical Phase II studies is 120 mg/m2 without G-CSF support and 200 mg/m2 with G-CSF support.

• Authors: I Rassmann, R Thödtmann, M Mross, A Hüttmann, W E Berdel, C Manegold, H H Fiebig, A Kaeser-Fröhlich, K Burk, A R Hanauske
• Journal: Investigational new drugs (Invest New Drugs) 1998-1999 Vol. 16 Issue 4 Pg. 319-24 ISSN: 0167-6997 [Print] United States
• PMID: 10426664 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• NK 611
• Granulocyte Colony-Stimulating Factor
• Podophyllotoxin

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Area Under Curve
• Cohort Studies
• Female
• Granulocyte Colony-Stimulating Factor (administration & dosage)
• Humans
• Infusions, Intravenous
• Male
• Middle Aged
• Neoplasms (drug therapy, metabolism)
• Podophyllotoxin (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)