title: Phase I and pharmacokinetic study of brostallicin (PNU-166196), a new DNA minor-groove binder, administered intravenously every 3 weeks to adult patients with metastatic cancer.
abstract: OBJECTIVE
  Brostallicin (PNU-166196) is a cytotoxic agent that binds to the minor groove of DNA with significant antitumor activity in preclinical studies. This trial was designed to determine the maximum tolerated dose, the toxicity profile, and the pharmacokinetics of Brostallicin in cancer patients.
  
  
  METHODS
  Patients were treated with escalating doses of Brostallicin ranging from 0.85 to 15 mg/m(2) administered as a 10-min i.v. infusion every 3 weeks. Blood samples for pharmacokinetic analysis were collected during the first and second course, and analyzed by liquid-chromatography with tandem-mass spectrometric detection.
  
  
  RESULTS
  Twenty-seven evaluable patients received a total of 73 courses. Grade 4 neutropenia was the only dose-limiting toxicity at 12.5 mg/m(2), whereas grade 4 thrombocytopenia (1 patient) and grade 4 neutropenia (2 patients) were the dose-limiting toxicities at 15 mg/m(2). Other side effects, including thrombocytopenia and nausea, were generally mild. The maximum tolerated dose was defined at 10 mg/m(2). The clearance and terminal half-life of Brostallicin were dose-independent, with mean (+/-SD) values of 9.33 +/- 2.38 liters/h/m(2) and 4.69 +/- 1.88 h, respectively. There was no significant accumulation of Brostallicin with repeated administration. Significant relationships were observed between systemic exposure to Brostallicin and neutrophil counts at nadir. One partial response was observed in a patient with a gastrointestinal stromal tumor.
  
  
  CONCLUSIONS
  Brostallicin was found to be well tolerated, with neutropenia being the principal toxicity. The recommended dose for additional evaluation in this schedule is 10 mg/m(2).
authors.affiliation: Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam 3075 EA, the Netherlands.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Ten Tije
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.forename: Ate
authors.initials: A
authors.lastname: Van Der Gaast
authors.forename: Camilla
authors.initials: C
authors.lastname: Fowst
authors.forename: Francesco
authors.initials: F
authors.lastname: Fiorentini
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tursi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Antonellini
authors.forename: Marijke
authors.initials: M
authors.lastname: Mantel
authors.forename: Carla M
authors.initials: CM
authors.lastname: Hartman
authors.forename: Gerrit
authors.initials: G
authors.lastname: Stoter
authors.forename: Andre S T
authors.initials: AS
authors.lastname: Planting
authors.forename: Maja J A
authors.initials: MJ
authors.lastname: De Jonge
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D004268:DNA-Binding Proteins; D005260:Female; D006146:Guanidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D007262:Infusions, Intravenous; D007364:Intercalating Agents / Q000494:pharmacology*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D004268:DNA-Binding Proteins; D006146:Guanidines; D007364:Intercalating Agents; D011758:Pyrroles; C455279:brostallicin