title: Phase I study of continuous weekly dosing of dimethylamino benzoylphenylurea (BPU) in patients with solid tumours.
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 320mg 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 320mg 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 150mg 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.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Building, CRB 1M88, 1650 Orleans Street, Baltimore, MD 21231, USA. wmesser1@jhmi.edu
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Connie
authors.initials: C
authors.lastname: Collins
authors.forename: A Dimitrios
authors.initials: AD
authors.lastname: Colevas
authors.forename: Ross C
authors.initials: RC
authors.lastname: Donehower
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Wolff
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008782:Methylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008874:Midazolam; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D008782:Methylurea Compounds; C496369:dimethyl benzoylphenyl urea; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam