title: A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours.
abstract: The aim of this study is to define the maximum tolerated dose (MTD), safety, pharmacokinetics (PKs) and efficacy of ispinesib (SB-715992) in combination with docetaxel. Patients with advanced solid tumours were treated with ispinesib (6-12 mg m(-2)) and docetaxel (50-75 mg m(-2)). Docetaxel was administered over 1 h followed by a 1-h infusion of ispinesib on day 1 of a 21-day schedule. At least three patients were treated at each dose level. Blood samples were collected during cycle 1 for PK analysis. Clinical response assessments were performed every two cycles using RECIST guidelines. Twenty-four patients were treated at four dose levels. Prolonged neutropaenia and febrile neutropaenia were dose limiting in six and two patients, respectively. The MTD was ispinesib 10 mg m(-2) with docetaxel 60 mg m(-2). Pharmacokinetic assessment demonstrated concentrations of ispinesib and docetaxel, consistent with published data from single agent studies of the drugs. Seven patients (six hormone refractory prostate cancer (HRPC), one renal cancer) had a best response of stable disease (>or=18 weeks). One patient with HRPC had a confirmed >50% prostatic-specific antigen decrease. The MTD for ispinesib and docetaxel was defined and the combination demonstrated an acceptable toxicity profile. Preliminary PK data suggest no interaction between ispinesib and docetaxel.
authors.affiliation: Royal Marsden Hospital and Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT, UK.
authors.forename: S P
authors.initials: SP
authors.lastname: Blagden
authors.forename: L R
authors.initials: LR
authors.lastname: Molife
authors.forename: A
authors.initials: A
authors.lastname: Seebaran
authors.forename: M
authors.initials: M
authors.lastname: Payne
authors.forename: A H M
authors.initials: AH
authors.lastname: Reid
authors.forename: A S
authors.initials: AS
authors.lastname: Protheroe
authors.forename: L S
authors.initials: LS
authors.lastname: Vasist
authors.forename: D D
authors.initials: DD
authors.lastname: Williams
authors.forename: C
authors.initials: C
authors.lastname: Bowen
authors.forename: S J
authors.initials: SJ
authors.lastname: Kathman
authors.forename: J P
authors.initials: JP
authors.lastname: Hodge
authors.forename: M M
authors.initials: MM
authors.lastname: Dar
authors.forename: J S
authors.initials: JS
authors.lastname: de Bono
authors.forename: M R
authors.initials: MR
authors.lastname: Middleton
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000077143:Docetaxel; D005260:Female; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D001549:Benzamides; C470243:KIF11 protein, human; D011799:Quinazolines; D043823:Taxoids; D000077143:Docetaxel; C508757:ispinesib; D016547:Kinesins