title: Phase I and pharmacokinetic study of continuous twice weekly intravenous administration of Cilengitide (EMD 121974), a novel inhibitor of the integrins alphavbeta3 and alphavbeta5 in patients with advanced solid tumours.
abstract: A single-agent dose escalating phase I and pharmacokinetic study with Cilengitide, an inhibitor of the integrins alphavbeta3 and alphavbeta5, was performed to determine its safety and toxicity. Cilengitide was administered as a one-hour infusion twice weekly without interruption to patients with histologically- or cytologically-confirmed metastatic solid tumours. Plasma pharmacokinetics were determined at days 1 and 15. 37 patients were enrolled into the study. Dose levels studied were 30, 60, 120, 180, 240, 400, 600, 850, 1200, and 1600 mg/m(2)/infusion. There was no dose-limiting toxicity (DLT). Pharmacokinetics were dose-independent and time-invariant. Apparent terminal half-life ranged from 3 to 5 h. At 120 mg/m(2)/infusion, peak plasma concentrations were attained that optimally inhibited tumour growth in preclinical models. Cilengitide can be safely administered using a continuous twice-weekly infusion regimen. As DLT was not reached, future trials should explore Cilengitide at different doses.
authors.affiliation: Erasmus Medical Center, Department of Medical Oncology, PO Box 2040, 3000 CA Rotterdam, The Netherlands. f.eskens@erasmusmc.nl
authors.forename: F A L M
authors.initials: FA
authors.lastname: Eskens
authors.forename: H
authors.initials: H
authors.lastname: Dumez
authors.forename: R
authors.initials: R
authors.lastname: Hoekstra
authors.forename: A
authors.initials: A
authors.lastname: Perschl
authors.forename: C
authors.initials: C
authors.lastname: Brindley
authors.forename: S
authors.initials: S
authors.lastname: Böttcher
authors.forename: W
authors.initials: W
authors.lastname: Wynendaele
authors.forename: J
authors.initials: J
authors.lastname: Drevs
authors.forename: J
authors.initials: J
authors.lastname: Verweij
authors.forename: A T
authors.initials: AT
authors.lastname: van Oosterom
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors; D016023:Integrins / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors; D012910:Snake Venoms / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D039302:Integrin alphaVbeta3; D016023:Integrins; D019030:Receptors, Vitronectin; D012910:Snake Venoms; C064660:integrin alphaVbeta5; C422910:Cilengitide