title: 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.
  
  
  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%.
  
  
  CONCLUSIONS
  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.affiliation: III. Medical Department, Klinikum r. d. Isar der Technischen Universität München, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Rassmann
authors.forename: R
authors.initials: R
authors.lastname: Thödtmann
authors.forename: M
authors.initials: M
authors.lastname: Mross
authors.forename: A
authors.initials: A
authors.lastname: Hüttmann
authors.forename: W E
authors.initials: WE
authors.lastname: Berdel
authors.forename: C
authors.initials: C
authors.lastname: Manegold
authors.forename: H H
authors.initials: HH
authors.lastname: Fiebig
authors.forename: A
authors.initials: A
authors.lastname: Kaeser-Fröhlich
authors.forename: K
authors.initials: K
authors.lastname: Burk
authors.forename: A R
authors.initials: AR
authors.lastname: Hanauske
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D015331:Cohort Studies; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011034:Podophyllotoxin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; C080080:NK 611; D016179:Granulocyte Colony-Stimulating Factor; D011034:Podophyllotoxin