Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors

Annals of Oncology. Published online on February 24, 2006 [Link]

H. Richly 1, B. F. Henning 2, P. Kupsch 1, K. Passarge 1, M. Grubert 1, R. A. Hilger 1, O. Christensen 3, E. Brendel 3, B. Schwartz 4, M. Ludwig 5, C. Flashar 6, R. Voigtmann 6, M. E. Scheulen 1, S. Seeber 1, and D. Strumberg 1 *

1 West German Cancer Center, University of Essen, Germany

2 Department of Gastroenterology and Internal Medicine, Marienhospital Herne, University of Bochum, Germany

3 Bayer HealthCare AG, Clinical Pharmacology, Wuppertal, Germany

4 Bayer Pharmaceuticals Corporation, West Haven, CT, USA

5 M.A.R.C.O. Institute for Clinical Research and Statistics – Dr. Wargenau, Düsseldorf, Germany

6 Department of Hematology and Medical Oncology, Marienhospital Herne, University of Bochum, Germany

* To whom correspondence should be addressed: D. Strumberg, E-mail:


Background: Sorafenib (BAY 43-9006), a novel, oral multi-kinase inhibitor, blocks serine/threonine and receptor tyrosine kinases in the tumor and vasculature. Sorafenib demonstrated single-agent activity in Phase I studies, and was tolerated and inhibited tumor growth in combination with doxorubicin in preclinical studies. This Phase I dose-escalation study determined the safety, pharmacokinetics and efficacy of sorafenib plus doxorubicin.

Patients and methods: Thirty-four patients with refractory, solid tumors received doxorubicin 60 mg/m2 on Day 1 of 3-week cycles, and oral sorafenib from Day 4 of Cycle 1 at 100, 200 or 400 mg bid.

Results: Common drug-related adverse events were neutropenia (56%), hand-foot skin reaction (44%), stomatitis (32%), and diarrhea (32%). The maximum tolerated dose was not reached. One patient with pleural mesothelioma achieved a partial response (modified WHO criteria) and remained on therapy for 39.7 weeks. Fifteen patients (48%) achieved stable disease for >= 12 weeks. Doxorubicin exposure increased moderately with sorafenib 400 mg bid. The pharmacokinetics of sorafenib and doxorubicinol were not affected.

Conclusion: Sorafenib 400 mg bid plus doxorubicin 60 mg/m2 was well tolerated. The increased doxorubicin exposure with sorafenib 400 mg bid did not result in significantly increased toxicity; low patient numbers make the clinical significance of this unclear. These promising efficacy results justify further clinical investigation.

Keywords: BAY 43-9006; doxorubicin; Phase I; Raf kinase; sorafenib.