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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.

AbstractPURPOSE:
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.
EXPERIMENTAL DESIGN:
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.
CONCLUSION:
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).
AuthorsAlbert J Ten Tije, Jaap Verweij, Alex Sparreboom, Ate Van Der Gaast, Camilla Fowst, Francesco Fiorentini, Jennifer Tursi, Alessandro Antonellini, Marijke Mantel, Carla M Hartman, Gerrit Stoter, Andre S T Planting, Maja J A De Jonge
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 9 Issue 8 Pg. 2957-64 (Aug 01 2003) ISSN: 1078-0432 [Print] United States
PMID12912942 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)
Chemical References
  • DNA-Binding Proteins
  • Guanidines
  • Intercalating Agents
  • Pyrroles
  • brostallicin
Topics
  • Adult
  • Aged
  • Area Under Curve
  • DNA-Binding Proteins
  • Female
  • Guanidines (administration & dosage, pharmacokinetics, therapeutic use)
  • Humans
  • Infusions, Intravenous
  • Intercalating Agents (pharmacology)
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Models, Chemical
  • Neoplasms (drug therapy)
  • Pyrroles (administration & dosage, pharmacokinetics, therapeutic use)

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