Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours

• Published in: British journal of cancer 2005-05, Vol.92 (10), p.1855-1861
• Main Authors: Awada, A, Hendlisz, A, Gil, T, Bartholomeus, S, Mano, M, de Valeriola, D, Strumberg, D, Brendel, E, Haase, C G, Schwartz, B, Piccart, M
• Format: Article
• Language: English
• Subjects: Adult; Aged; Benzenesulfonates - administration & dosage; Benzenesulfonates - adverse effects; Benzenesulfonates - pharmacokinetics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Renal Cell - drug therapy; Clinical Study; Drug Administration Schedule; Drug Resistance; Epidemiology; Female; Humans; Kidney Neoplasms - drug therapy; Male; Maximum Tolerated Dose; Medical sciences; Middle Aged; Molecular Medicine; Neoplasms - drug therapy; Niacinamide - analogs & derivatives; Oncology; Phenylurea Compounds; Pyridines - administration & dosage; Pyridines - adverse effects; Pyridines - pharmacokinetics; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6602584

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.