title: 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.
abstract: OBJECTIVE
  BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor inhibitor that inhibits tumor cell proliferation and angiogenesis. This study established the safety and pharmacokinetics of BAY 43-9006 in 69 patients with advanced refractory solid tumors.
  
  
  METHODS
  BAY 43-9006 (50 to 800 mg) was administered once or twice daily on a varying weekly schedule. Pharmacokinetic sampling was performed in all patients; preliminary tumor response was also assessed. The effect of BAY 43-9006 on phorbol myristate acetate-stimulated ERK phosphorylation in peripheral blood lymphocytes was studied using flow cytometry.
  
  
  RESULTS
  Mild to moderate diarrhea was the most common (55%) treatment-related adverse event. The maximum-tolerated dose was 400 mg bid continuous. Dose-limiting toxicities were grade 3 diarrhea and fatigue at 800 mg bid, and grade 3 skin toxicity at 600 mg bid. BAY 43-9006 pharmacokinetics were highly variable for single and multiple dosing, and toxicity did not appear to be dose dependent. Significant decreases of phorbol myristate acetate-stimulated ERK phosphorylation (P < .01) were identified at doses >/= 200 mg bid continuous. Forty-five patients were assessable for efficacy; one patient had a partial response (hepatocellular carcinoma at 400 mg bid continuous), 25 patients had stable disease, with eight lasting > 6 months and five for >12 months. Eighteen patients had progressive disease, and tumor response could not be evaluated in one patient.
  
  
  CONCLUSIONS
  Oral BAY 43-9006 was well tolerated and appeared to provide some clinical benefits. Based on the results of this study, BAY 43-9006 at 400 mg bid continuous is recommended for ongoing and future studies.
authors.affiliation: Department of Internal Medicine and Medical Oncology, West German Cancer Center, University Medical School of Essen, Germany. dirk.strumberg@uni-essen.de
authors.forename: Dirk
authors.initials: D
authors.lastname: Strumberg
authors.forename: Heike
authors.initials: H
authors.lastname: Richly
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Hilger
authors.forename: Norbert
authors.initials: N
authors.lastname: Schleucher
authors.forename: Sonke
authors.initials: S
authors.lastname: Korfee
authors.forename: Mitra
authors.initials: M
authors.lastname: Tewes
authors.forename: Markus
authors.initials: M
authors.lastname: Faghih
authors.forename: Erich
authors.initials: E
authors.lastname: Brendel
authors.forename: Dimitris
authors.initials: D
authors.lastname: Voliotis
authors.forename: Claus G
authors.initials: CG
authors.lastname: Haase
authors.forename: Brian
authors.initials: B
authors.lastname: Schwartz
authors.forename: Ahmad
authors.initials: A
authors.lastname: Awada
authors.forename: Rudolf
authors.initials: R
authors.lastname: Voigtmann
authors.forename: Max E
authors.initials: ME
authors.lastname: Scheulen
authors.forename: Siegfried
authors.initials: S
authors.lastname: Seeber
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001557:Benzenesulfonates / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy; D015331:Cohort Studies; D003110:Colonic Neoplasms / Q000188:drug therapy; D003967:Diarrhea / Q000139:chemically induced; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D049488:Phosphatidylethanolamine Binding Protein / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D012004:Rectal Neoplasms / Q000188:drug therapy; D012449:Safety; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D049488:Phosphatidylethanolamine Binding Protein; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D040262:Receptors, Vascular Endothelial Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases