Annals of Oncology Advance Access originally published online on July 8, 2005
Annals of Oncology 2005 16(10):1688-1694; doi:10.1093/annonc/mdi310
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© 2005 European Society for Medical Oncology
Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors
1 Princess Margaret Hospital, Toronto, Ontario; 2 Juravinski Cancer Centre, Hamilton, Ontario; 3 Bayer Inc., Toronto, Canada; 4 Bayer Pharmaceuticals Corporation, West Haven, CT, USA
* Correspondence to: Dr M. J. Moore, Princess Margaret Hospital, 5th Floor Rm 5-205, 610 University Avenue, Toronto, Ontario Canada M5G 2M9. Tel: +1 416-946-2263; Fax: +1 416-946-2082; E-mail: malcolm.moore{at}uhn.on.ca
Background: BAY 43-9006, an oral multi-kinase inhibitor, targets serine-threonine kinases and receptor tyrosine kinases, and affects the tumor and vasculature in preclinical models. Based on its pharmacologic effect, it may be a useful cancer treatment. This study determined the maximum tolerated dose (MTD) of BAY 43-9006 in 42 patients with advanced, refractory metastatic or recurrent solid tumors. Dose-limiting toxicities (DLTs), safety, pharmacokinetics and tumor response were also evaluated.
Patients and methods: In this open-label, phase I, dose-escalation study, BAY 43-9006 was administered orally in repeated cycles of 35 days (28 days on/7 days off). Eight doses were investigated: from 50 mg every fourth day to 600 mg twice daily. Treatment continued until unacceptable toxicity, tumor progression or death.
Results: The MTD was 400 mg twice daily. BAY 43-9006 was well tolerated, with mild to moderate toxicities; only six patients discontinued study therapy due to adverse events. DLTs consisted of hand–foot skin reaction in three of seven patients receiving 600 mg twice daily. Stable disease was achieved in 22% of patients; median duration of stable disease was 7.2 months. Consistent with its observed half-life of 
27 h, BAY 43-9006 accumulated on multiple dosing. Increases in exposure were less than proportional to the increases in dose.
Conclusions: Results indicate that further clinical investigation of BAY 43-9006 is warranted, and suggest it could be a promising future therapy for patients with cancer.
Key words: BAY 43-9006, pharmacokinetics, phase I, safety
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