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Phase II Study of the Flk-1 Tyrosine Kinase Inhibitor SU5416 in Advanced Melanoma

¹ Department of Medicine, Section of Hematology/Oncology, ² University of Chicago Cancer Research Center, ³ Department of Surgery, Section of Urology, ⁴ Department of Radiology, and ⁵ Department of Pathology, The University of Chicago, Chicago, Illinois

Purpose: Vascular endothelial growth factor (VEGF) expression is prognostic in melanoma, and the activity of VEGF is mediated in part through the receptor tyrosine kinase Flk-1. A Phase II study of SU5416, a preferential inhibitor of Flk-1, was carried out in patients with metastatic melanoma to determine clinical response, tolerability, and changes in tumor vascular perfusion.

Experimental Design: Patients with documented progressive disease and 1 prior therapy were eligible. Central nervous system metastases were allowed if stable off medication. SU5416 (145 mg/m²) was administered via a central catheter twice weekly for 8 weeks. Premedication with dexamethasone, diphenhydramine, and a H₂ blocker was required because of the Cremophor vehicle. Tumor vascular perfusion was assessed before treatment and during week 8 by dynamic contrast magnetic resonance imaging, and plasma was analyzed for VEGF.

Results: Thirty-one patients were enrolled. Two-thirds had received prior therapy, 21 had visceral metastasis, and 14 had an elevated lactate dehydrogenase. Mean absolute lymphocyte counts were decreased (P = 0.002), and glucose levels were increased (P = 0.001) posttherapy, presumably because of steroid premedication. Four vascular adverse events were observed. Of 26 evaluable patients, 1 experienced a partial response, 1 had stable disease, and 5 had a mixed response. Dynamic contrast magnetic resonance imaging in 5 evaluable patients showed decreased tumor perfusion at week 8 (P = 0.024), and plasma VEGF levels were elevated compared with pretherapy (P = 0.008).

Conclusions: SU5146 appears to be relatively well tolerated in this population. Although the modest clinical activity and potential effects on tumor vascularity may support additional exploration of VEGF as a target in melanoma, effects from steroid premedication limit further investigation of this agent.

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