Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors.

PURPOSE: BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor inhibitor that inhibits tumor cell proliferation and angiogenesis. This study established the safety and pharmacokinetics of BAY 43-9006 in 69 patients with advanced refractory solid tumors. PATIENTS AND METHODS: BAY 43-9006 (50 to 800 mg) was administered once or twice daily on a varying weekly schedule. Pharmacokinetic sampling was performed in all patients; preliminary tumor response was also assessed. The effect of BAY 43-9006 on phorbol myristate acetate-stimulated ERK phosphorylation in peripheral blood lymphocytes was studied using flow cytometry. RESULTS: Mild to moderate diarrhea was the most common (55%) treatment-related adverse event. The maximum-tolerated dose was 400 mg bid continuous. Dose-limiting toxicities were grade 3 diarrhea and fatigue at 800 mg bid, and grade 3 skin toxicity at 600 mg bid. BAY 43-9006 pharmacokinetics were highly variable for single and multiple dosing, and toxicity did not appear to be dose dependent. Significant decreases of phorbol myristate acetate-stimulated ERK phosphorylation (P < .01) were identified at doses >/= 200 mg bid continuous. Forty-five patients were assessable for efficacy; one patient had a partial response (hepatocellular carcinoma at 400 mg bid continuous), 25 patients had stable disease, with eight lasting > 6 months and five for >12 months. Eighteen patients had progressive disease, and tumor response could not be evaluated in one patient. CONCLUSION: Oral BAY 43-9006 was well tolerated and appeared to provide some clinical benefits. Based on the results of this study, BAY 43-9006 at 400 mg bid continuous is recommended for ongoing and future studies.

New approaches for small-cell lung cancer: local treatments.

BACKGROUND: Limited-disease small-cell lung cancer (LD-SCLC) can be cured with combinations of systemic chemotherapy and local treatments, predominantly radiation therapy. While systemic control inside the brain has been further improved with the inclusion of prophylactic cranial irradiation, long-term local control remains suboptimal, even with newer chemoradiation protocols. METHODS: The authors review the current management of LD-SCLC and discuss strategies to improve local control. They present their own experience with the inclusion of surgery in an aggressive combined-modality protocol for patients with LD-SCLC. RESULTS: Different approaches to improve local efficacy of treatment have been explored, including concurrent chemoradiation, administration of radiation as early as possible, newer fractionation schemas, and escalation of overall radiation doses. However, even following the currently most active chemoradiation protocols, local and locoregional relapse of LD-SCLC remains a problem. Surgery is feasible within this clinical setting and may add to long-term local control and possible cures. CONCLUSIONS: Further investigation into the inclusion of surgery in LD-SCLC within carefully designed prospective clinical trials seems justified, although final evaluation would necessarily include prospective, randomized testing within a more "modernized" study design compared to the "old" and "historical" randomized Lung Cancer Study Group trial.