title: Phase I study of docetaxel and topotecan in patients with advanced malignancies.
abstract: BACKGROUND
  Docetaxel and topotecan are drugs with different mechanisms of action and significant activity against various tumour types. Topotecan may influence docetaxel metabolism by inhibiting the CYP3A4 enzyme. We designed a phase I study to evaluate the maximum tolerated dose of this combination and to assess the impact of pharmacokinetic interactions of the two drugs on toxicity.
  
  
  METHODS
  Docetaxel and topotecan were administered intravenously on day 1, and days 1 - 5 respectively, using a phase I dose escalation design. Plasma samples were analysed to determine docetaxel and topotecan concentration by HPLC with subsequent pharmacokinetic analysis using NONMEM.
  
  
  RESULTS
  Of the 17 patients enrolled in the trial, 11 had grade 3 and 4 neutropenia and 1 had grade 4 thrombocytopenia. Nonhaematological toxicities were less frequent. The maximum tolerated dose for docetaxel and topotecan were 60 mg/m(2) on day 1 and 0.75 mg/m(2) days 1 - 5, respectively. One patient had stable disease. Subjects with grade >or= 3 haematologic toxicity had higher plasma docetaxel or topotecan area under the curve (AUC) (docetaxel 1.03 +/- 0.11 mg-hr/L versus 0.73 +/- 0.13 mg-hr/L; topotecan 65.8 +/- 14.6 mcg-hr/L versus 41.6 +/- 13.9 mcg-hr/L). There was no additive effect of the AUC of the two drugs on the likelihood of grade >or= 3 haematologic toxicity by multiple logistic regression.
  
  
  CONCLUSIONS
  The dose-limiting toxicity seen with the combination of docetaxel and topotecan was myelosuppression. Future trials will require growth factor support if this combination is pursued.
authors.affiliation: Department of Medicine, Medical Oncology Section, University of Wisconsin Comprehensive Cancer Center, Madison, USA. sd@medicine.wisc.edu
authors.forename: Sarita
authors.initials: S
authors.lastname: Dubey
authors.forename: Paul
authors.initials: P
authors.lastname: Hutson
authors.forename: Dona
authors.initials: D
authors.lastname: Alberti
authors.forename: Rhoda
authors.initials: R
authors.lastname: Arzoomanian
authors.forename: Kim
authors.initials: K
authors.lastname: Binger
authors.forename: Jennifer
authors.initials: J
authors.lastname: Volkman
authors.forename: Chris
authors.initials: C
authors.lastname: Feierabend
authors.forename: George
authors.initials: G
authors.lastname: Wilding
authors.forename: Joan H
authors.initials: JH
authors.lastname: Schiller
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013921:Thrombocytopenia / Q000139:chemically induced; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D019772:Topotecan