This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Duran, I. Articles by Siu, L. L. Search for Related Content PubMed PubMed Citation Articles by Duran, I. Articles by Siu, L. L.

Phase I Targeted Combination Trial of Sorafenib and Erlotinib in Patients with Advanced Solid Tumors

Authors' Affiliations: ¹ Princess Margaret Hospital Phase II Consortium; ² Division of Dermatology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; ³ Bayer Pharmaceuticals Corp., West Haven, Connecticut; and ⁴ National Cancer Institute, Bethesda, Maryland

Requests for reprints: Lillian L. Siu, Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, 610 University Avenue, Suite 5-718, Toronto, Ontario, Canada M5G 2M9. Phone: 416-946-2911; Fax: 416-946-4467; E-mail: lillian.siu{at}uhn.on.ca.

Purpose: Sorafenib and erlotinib are potent, orally administered receptor tyrosine kinase inhibitors with antiproliferative and antiangiogenic activities. Given their inhibitory target profile and efficacy as single agents, the combination of these drugs is of considerable interest in solid malignancies. This study aimed to determine the recommended phase II dose of this targeted combination, their toxicity profile, pharmacokinetic interaction, and preliminary clinical activities.

Experimental Design: Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously, with every 28 days considered as a cycle. Three dose levels were assessed.

Results: Seventeen patients with advanced solid tumors received 75 cycles of treatment. The most frequent adverse events of all grades were constitutional and gastrointestinal in nature followed by electrolytes and dermatologic toxicities. Fatigue was the most common adverse event (17 patients; 100%) followed by diarrhea (15 patients; 88%), hypophosphatemia (13 patients; 76%), and acneiform rash (12 patients; 71%). These adverse events were predominantly mild to moderate. The recommended phase II dose of this combination was determined as 400 mg twice daily sorafenib and 150 mg daily erlotinib. Pharmacokinetic analysis revealed no significant effect of erlotinib on the pharmacokinetic profile of sorafenib. Among 15 evaluable patients, 3 (20%) achieved a confirmed partial response and 9 (60%) had stable disease as best response.

Conclusions: Sorafenib and erlotinib are well tolerated and seem to have no pharmacokinetic interactions when administered in combination at their full single-agent recommended doses. This well tolerated combination resulted in promising activity that needs further validation in phase II studies.