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.
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.
Strumberg
Dirk
D
Department of Internal Medicine and Medical Oncology, West German Cancer Center, University Medical School of Essen, Germany. dirk.strumberg@uni-essen.de
Richly
Heike
H
Hilger
Ralf A
RA
Schleucher
Norbert
N
Korfee
Sonke
S
Tewes
Mitra
M
Faghih
Markus
M
Brendel
Erich
E
Voliotis
Dimitris
D
Haase
Claus G
CG
Schwartz
Brian
B
Awada
Ahmad
A
Voigtmann
Rudolf
R
Scheulen
Max E
ME
Seeber
Siegfried
S
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
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