Abstract
Background: NK611 is a novel podophyllotoxin derivative. Compared with etoposide, NK611 carries a dimethyl-amino 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 (t1/2γ) was 14.7 ± 3.7 h. The AUC at 250 mg/m2 was determined to be 330 ± 147 μg/mlh, the plasma clearance of NK611 was 16.2 ± 8.2 ml/min · m2 and the Vss 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.
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Machida M, Tanaka S, Nakamori K et al.: Simultaneous determination of NK611, a novel water-soluble derivative of etoposide, and its metabolite (DeNK611) in dogs plasma by column-switching high performance chromatography. Biomedic Chromatograph 7: 82-85, 1993
Asta Medica GmbH: Investigator's drug brochure: NK611. Asta Medica GmbH. 1993; p. 35
Ekimoto H, Okamoto K, Maruyma S et al.: Preclinical characterization of NK611, a novel water-soluble etoposide analog. Ann Oncol 3 (Suppl 1): 98, 1992
Hanauske A-R, Wüster KC, Lehmer A et al.: Activity of NK611, a new epipodophyllotoxin derivative, against colony forming units from freshly explanted human tumors in vitro. Eur J Cancer 31A: 1677-1681, 1995
Ekimoto H, Okamoto K, Kusuma K et al.: Treatment schedule dependency of antitumor effects of NK611, a novel watersoluble analog of etoposide, on human xenografts. Proc Amer Assoc Cancer Res 33: 436, 1992
Pagani O, Zucchetti M, Sessa C et al.: Phase I clinical and pharmacokinetic study of oral NK611, a new podophyllotoxin derivative. Cancer Chemother Pharmacol 38: 541-547, 1996
Rassmann I, Schrödel H, Schilling T et al.: Clinical and pharmacokinetic Phase I trial of oral dimethylaminoetoposide (NK611) administered for 21 days every 35 days. Invest New Drugs 14: 379-386, 1996
Schilling T, Mross K, Berdel WE et al.: Phase I clinical and pharmacokinetic trial of the podophyllotoxin derivative NK611. Ann Oncol 5 (Suppl 5): 193, 1994
Hüttmann A, Mross K, Hossfeld DK et al.: Determination of the new epidophyllotoxin derivative NK-611 in plasma by high-performance liquid chromatography with ultraviolet detection. J Chromatogr 620: 233-238, 1993
Mross K, Hüttmann A, Herbst K et al.: Pharmacokinetics and pharmacodynamics of the new podophyllotoxin derivative NK611. Cancer Chemother Pharmacol 38: 217-224, 1996
Stewart CF, Ratain MJ: Topoisomerase interactive agents. In: DeVita VT, Jr, Hellman S et al.: Cancer Principles and Practice of Oncology, 5th Ed., Lippincott-Raven Publ 1997, p 456
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Rassmann, I., Thödtmann, R., Mross, M. et al. Phase I clinical and pharmacokinetic trial of the podophyllotoxin derivative NK611 administered as intravenous short infusion. Invest New Drugs 16, 319–324 (1998). https://doi.org/10.1023/A:1006293830585
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DOI: https://doi.org/10.1023/A:1006293830585