title: Phase I and pharmacokinetic study of the dolastatin 10 analogue TZT-1027, given on days 1 and 8 of a 3-week cycle in patients with advanced solid tumors.
abstract: OBJECTIVE
  TZT-1027 [N(2)-(N,N-dimethyl-l-valyl)-N-[(1S,2R)-2-methoxy-4-[(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-[(2-phenylethyl)]amino]propyl]-1-pyrrolidinyl]-1-[(S)-1-methylpropyl]-4-oxobutyl]-N-methyl-l-valinamide] is a cytotoxic dolastatin 10 derivative inhibiting microtubule assembly through the binding to tubulins. The objectives of this phase I study was to assess the dose-limiting toxicities (DLT), to determine the maximum tolerated dose, and to study the pharmacokinetics of TZT-1027 when given i.v. over 60 minutes on days 1 and 8 every 3 weeks to patients with advanced solid tumors.
  
  
  METHODS
  Patients were treated with escalating doses of TZT-1027 at doses ranging from 1.35 to 2.7 mg/m(2). For pharmacokinetic analysis, plasma sampling was done during the first and second course and assayed using a validated high-performance liquid chromatographic assay with mass spectrometric detection.
  
  
  RESULTS
  Seventeen patients received a total of >70 courses. The stopping dose was reached at 2.7 mg/m(2), with neutropenia and infusion arm pain as DLT. Neutropenia was not complicated by fever. Over all dose levels, eight patients experienced pain in the infusion arm 1 to 2 days after administration of the drug, which seemed ameliorated by adding additional flushing after drug administration. Other side effects included nausea, vomiting, diarrhea, and fatigue. One partial response lasting >54 weeks was observed in an extensively pretreated patient with metastatic liposarcoma. The pharmacokinetics of TZT-1027 suggested linearity over the dose ranges. No correlation between body surface area and absolute CL of TZT-1027 was established, vindicating that a flat dosing regimen might be used in the future. A correlation was observed between the percentage decrease in neutrophil count and the AUC of TZT-1027.
  
  
  CONCLUSIONS
  In this study, the DLT of TZT-1027 was neutropenia and infusion arm pain. The recommended dose for phase II studies of TZT-1027 is 2.4 mg/m(2) given i.v. over 60 minutes, on days 1 and 8 every 21 days. Phase II studies have recently started.
authors.affiliation: Erasmus University Medical Center/Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. m.dejonge@erasmusc.nl
authors.forename: Maja J A
authors.initials: MJ
authors.lastname: de Jonge
authors.forename: Ate
authors.initials: A
authors.lastname: van der Gaast
authors.forename: André S T
authors.initials: AS
authors.lastname: Planting
authors.forename: Leny
authors.initials: L
authors.lastname: van Doorn
authors.forename: Aletta
authors.initials: A
authors.lastname: Lems
authors.forename: Inge
authors.initials: I
authors.lastname: Boot
authors.forename: Jantien
authors.initials: J
authors.lastname: Wanders
authors.forename: Masahiko
authors.initials: M
authors.lastname: Satomi
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; C105791:soblidotin