title: Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours.
abstract: BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor (VEGFR) inhibitor that targets tumour cell proliferation and tumour angiogenesis. This Phase I study was undertaken to determine the safety profile, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and tumour response profile of oral BAY 43-9006 in patients with advanced, refractory solid tumours. BAY 43-9006 was administered daily for repeated cycles of 21 days on/7 days off. A total of 44 patients were enrolled at doses from 50 to 800 mg b.i.d. Pharmacokinetic profiles of BAY 43-9006 in plasma were determined during the first treatment cycle. The most frequently reported adverse events over multiple cycles were gastrointestinal (75%), dermatologic (71%), constitutional (68%), pain (64%), or hepatic (61%) related. A MTD of 400 mg b.i.d. BAY 43-9006 was defined. BAY 43-9006 was absorbed rapidly; steady-state conditions were reached within 7 days. BAY 43-9006 exposure increased nonproportionally with increasing dose. In all, 32 patients were evaluated for tumour response: 15 patients showed tumour progression, 16 patients experienced stable disease (>6 months in eight patients), and one patient with renal cell carcinoma achieved a partial response. BAY 43-9006 given for 21 days with 7 days off treatment was safe, well tolerated, and showed antitumour activity.
authors.affiliation: Jules Bordet Institute, Brussels, Belgium. ahmad.awada@bordet.be
authors.forename: A
authors.initials: A
authors.lastname: Awada
authors.forename: A
authors.initials: A
authors.lastname: Hendlisz
authors.forename: T
authors.initials: T
authors.lastname: Gil
authors.forename: S
authors.initials: S
authors.lastname: Bartholomeus
authors.forename: M
authors.initials: M
authors.lastname: Mano
authors.forename: D
authors.initials: D
authors.lastname: de Valeriola
authors.forename: D
authors.initials: D
authors.lastname: Strumberg
authors.forename: E
authors.initials: E
authors.lastname: Brendel
authors.forename: C G
authors.initials: CG
authors.lastname: Haase
authors.forename: B
authors.initials: B
authors.lastname: Schwartz
authors.forename: M
authors.initials: M
authors.lastname: Piccart
mesh_terms: D000328:Adult; D000368:Aged; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000077157:Sorafenib
chemical_list: D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib