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: dirk.strumberg@marienhospital-herne.de

Abstract

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.