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Phase I trial of sorafenib in combination with gefitinib in patients with refractory or recurrent non-small cell lung cancer.

Research paper by Alex A AA Adjei, Julian R JR Molina, Sumithra J SJ Mandrekar, Randolph R Marks, Joel R JR Reid, Gary G Croghan, Lorelei J LJ Hanson, James R JR Jett, Chenghua C Xia, Chetan C Lathia, Ronit R Simantov

Indexed on: 03 May '07Published on: 03 May '07Published in: Clinical cancer research : an official journal of the American Association for Cancer Research



Abstract

To evaluate the combination of sorafenib and gefitinib in patients with advanced non-small cell lung cancer.In this dose-escalation trial, patients received oral sorafenib (200-400 mg) twice daily with gefitinib (250 mg orally) once daily to identify the recommended dose for phase II trials (RDP; part A). The pharmacokinetics of the RDP were characterized further in additional patients (part B) receiving single-agent gefitinib or sorafenib for 21 days followed by a 7-day washout with crossover to the other agent for an additional 21 days. Patients then received the combination of sorafenib plus gefitinib in 28-day cycles. Safety, pharmacokinetics, and antitumor efficacy were evaluated. Potential drug-drug interactions and the relationship between pharmacokinetics and toxicity were also assessed.Thirty-one patients were treated (n=12, part A; n=19, part B). Most adverse events were grade 1/2. The most frequent grade 3/4 events included diarrhea and elevated alanine aminotransferase (both 9.7%). One dose-limiting toxicity occurred (part A: elevated alanine aminotransferase at 400 mg twice daily). Gefitinib had no effect on sorafenib pharmacokinetics. However, gefitinib C(max) (26%) and area under the curve (38%) were reduced by concomitant sorafenib. One patient had a partial response; 20 (65%; n=8, part A; n=12, part B) had stable disease >or=4 months. The RDP was sorafenib 400 mg twice daily with gefitinib 250 mg once daily.Sorafenib combined with gefitinib is well tolerated, with promising efficacy in patients with advanced non-small cell lung cancer. Studies to further investigate the significance of the reduction in gefitinib exposure by sorafenib are warranted.

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