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A Phase I Trial of the Oral, Multikinase Inhibitor Sorafenib in Combination with Carboplatin and Paclitaxel

Authors' Affiliations: ¹ The Abramson Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania; ² University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin; ³ Cancer Research UK, Cambridge Research Institute, Cambridge, UK ⁴ Bayer Healthcare Pharmaceuticals Division, West Haven, Connecticut; ⁵ Bayer, Inc., Toronto, Ontario, Canada; ⁶ Fred Hutchinson Cancer Research Center, Seattle, Washington ⁷ Department of Otorhinolaryngology, Head & Neck Surgery, University of Pennsylvania, Philadelphia, PA; and ⁸ Glaxo SmithKline, Philadelphia, PA

Requests for reprints: Keith T. Flaherty, The Abramson Cancer Center of the University of Pennsylvania, 12 Penn Tower, 34th and Spruce Streets, Philadelphia, PA 19104. Phone: 215-662-7402; Fax: 215-349-8550. E-mail: ktflaherty{at}aol.com.

Purpose: This study evaluated the safety, maximum tolerated dose, pharmacokinetics, and antitumor activity of sorafenib, a multikinase inhibitor, combined with paclitaxel and carboplatin in patients with solid tumors.

Patients and Methods: Thirty-nine patients with advanced cancer (24 with melanoma) received oral sorafenib 100, 200, or 400 mg twice daily on days 2 to 19 of a 21-day cycle. All patients received carboplatin corresponding to AUC6 and 225 mg/m² paclitaxel on day 1. Pharmacokinetic analyses were done for sorafenib on days 2 and 19 of cycle 1 and for paclitaxel on day 1 of cycles 1 and 2. Pretreatment tumor samples from 17 melanoma patients were analyzed for BRAF mutations.

Results: Sorafenib was well tolerated at the doses evaluated. The most frequent severe adverse events were hematologic toxicities (grade 3 or 4 in 33 patients, 85%). Twenty-seven (69%) patients had sorafenib-related adverse events, the most frequent of which were dermatologic events (26 patients, 67%). Exposure to paclitaxel was not altered by intervening treatment with sorafenib. Treatment with sorafenib, paclitaxel, and carboplatin resulted in one complete response and nine partial responses, all among patients with melanoma. There was no correlation between BRAF mutational status and treatment responses in patients with melanoma.

Conclusions: The recommended phase II doses are oral 400 mg twice daily sorafenib, carboplatin at an AUC6 dose, and 225 mg/m² paclitaxel. The tumor responses observed with this combined regimen in patients with melanoma warrant further investigation.

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