Phase I Clinical and Pharmacokinetic Study of the Novel Raf Kinase and Vascular Endothelial Growth Factor Receptor Inhibitor BAY 43-9006 in Patients With Advanced Refractory Solid Tumors

• DOI: 10.1200/jco.2005.06.124
• Publication Date: 2004-12-22T03:00:17Z
• Authors: Dirk Strumberg; Heike Richly; Ralf A. Hilger; Norbert Schleucher; Sonke Korfee; Mitra Tewes; Markus Faghih; Erich Brendel; Dimitris Voliotis; Claus G. Haase; Brian Schwartz; Ahmad Awada; Rudolf Voigtmann; Max E. Scheulen; Siegfried Seeber
• Keywords: Male; Rectal Neoplasms -- drug therapy; Benzenesulfonates -- pharmacokinetics; Phosphatidylethanolamine Binding Protein -- adverse effects; Pyridines -- pharmacokinetics; Phosphatidylethanolamine Binding Protein; Phosphatidylethanolamine Binding Protein -- administration & dosage; Phosphatidylethanolamine Binding Protein -- pharmacokinetics; Protein Kinase Inhibitors -- pharmacokinetics; Cohort Studies; 0302 clinical medicine; Benzenesulfonates -- administration & dosage; Receptors; Pyridines -- administration & dosage; Lymphocytes; Protein Kinase Inhibitors -- adverse effects; Extracellular Signal-Regulated MAP Kinases; Fatigue; Hepatocellular -- drug therapy; Benzenesulfonates; Liver Neoplasms; Protein Kinase Inhibitors -- administration & dosage; Sciences bio-médicales et agricoles; Middle Aged; 3. Good health; Colonic Neoplasms -- drug therapy; Lymphocytes -- drug effects; Colonic Neoplasms; Liver Neoplasms -- drug therapy; Female; Safety; Lymphocytes -- enzymology; Adult; Diarrhea; Niacinamide; Carcinoma, Hepatocellular; Vascular Endothelial Growth Factor -- antagonists & inhibitors; Adolescent; Antineoplastic Agents; 03 medical and health sciences; Antineoplastic Agents -- administration & dosage; Extracellular Signal-Regulated MAP Kinases -- drug effects; Humans; Aged; Fatigue -- chemically induced; Phosphorylation -- drug effects; Phenylurea Compounds; Carcinoma; Antineoplastic Agents -- adverse effects; Antineoplastic Agents -- pharmacokinetics; Diarrhea -- chemically induced

BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor inhibitor that inhibits tumor cell proliferation angiogenesis. This study established the safety pharmacokinetics of in 69 patients with advanced refractory solid tumors.BAY (50 to 800 mg) was administered once or twice daily on varying weekly schedule. Pharmacokinetic sampling performed all patients; preliminary response also assessed. The effect phorbol myristate acetate-stimulated ERK phosphorylation peripheral blood lymphocytes studied using flow cytometry.Mild moderate diarrhea most common (55%) treatment-related adverse event. maximum-tolerated dose 400 mg bid continuous. Dose-limiting toxicities were grade 3 fatigue at bid, skin toxicity 600 bid. highly variable for single multiple dosing, did not appear be dependent. Significant decreases (P < .01) identified doses >/= 200 Forty-five assessable efficacy; one patient had partial (hepatocellular carcinoma continuous), 25 stable disease, eight lasting > 6 months five >12 months. Eighteen progressive could evaluated patient.Oral well tolerated appeared provide some clinical benefits. Based results this study, continuous recommended ongoing future studies.