Phase I study of continuous weekly dosing of dimethylamino benzoylphenylurea (BPU) in patients with solid tumours

Wells A. Messersmith, Michelle A. Rudek, Sharyn D. Baker, Ming Zhao, Connie Collins, A. Dimitrios Colevas, Ross C. Donehower, Michael A. Carducci, Antonio C. Wolff

Research output: Contribution to journalArticle

Abstract

A phase I study of dimethylamino benzoylphenylurea (BPU), a tubulin inhibitor, was performed using a weekly continuous schedule. Patients with refractory solid tumours received oral BPU once weekly without interruption at doses ranging from 5 to 320 mg using an accelerated titration design. Nineteen subjects received 54 cycles of BPU. Early pharmacokinetic findings of decreased clearance with increasing dose and plasma accumulation led to the expansion of the 320 mg dose level. Two subjects then developed late haematologic dose-limiting toxicities (DLTs) that were associated with the highest plasma exposure to BPU and metabolites. Study enrollment resumed at dose 150 mg with real-time pharmacokinetic monitoring. Seven additional subjects (6 evaluable) were treated for a median of 2 cycles (range 1.5-4) without further myelotoxicity. A long half-life and accumulation of BPU and active metabolites were observed, recommending against a continuous administration. Weekly oral BPU therapy should be further tested using an interrupted schedule.

Original languageEnglish (US)
Pages (from-to)78-86
Number of pages9
JournalEuropean Journal of Cancer
Volume43
Issue number1
DOIs
StatePublished - Jan 1 2007

Keywords

  • Accelerated titration introduction
  • Pharmacokinetics
  • Tubulin inhibitor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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