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A Randomized Phase 2 Trial of Bevacizumab with or without Daily Low-Dose Interferon Alfa-2b in Metastatic Malignant Melanoma

¹ Division of Surgical Oncology, The Ohio State University Comprehensive Cancer Center, N924 Doan Hall, 410 W 10th Avenue, Columbus, Ohio 43210, USA
² Clinical Trials Office, The Ohio State University Comprehensive Cancer Center, A075 Starling Loving Hall, 320 W 10th Avenue, Columbus, Ohio 43210, USA
³ Center for Biostatistics, The Ohio State University Comprehensive Cancer Center, M200 Starling Loving Hall, 320 W 20th Avenue, Columbus, Ohio 43210, USA
⁴ Department of Pathology, The Ohio State University Comprehensive Cancer Center, 185A Hamilton Hall, 1645 Neil Avenue, Columbus, Ohio 43210, USA
⁵ Division of Human Cancer Genetics, The Ohio State University Comprehensive Cancer Center, 302 Wiseman Hall, 400 W 12th Avenue, Columbus, Ohio 43210, USA
⁶ Division of Hematology and Oncology, The Ohio State University Comprehensive Cancer Center, B415 Starling Loving Hall, 320 W 10th Avenue, Columbus, Ohio 43210, USA
⁷ National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, Maryland, USA

Correspondence: Address correspondence and reprint requests to: William E. Carson III, MD; E-mail: William.Carson{at}osumc.edu

Background: Vascular endothelial growth factor (VEGF) is a proangiogenic molecule produced by melanoma cells. We hypothesized that administration of bevacizumab (Bev), a monoclonal antibody that neutralizes VEGF, with low-dose interferon alfa-2b (IFN-2b), an inhibitor of basic fibroblast growth factor (FGF), would lead to the regression of metastatic melanoma.

Methods: Patients with metastatic melanoma were randomized to receive Bev (15 mg/kg intravenously every 2 weeks) with or without low-dose IFN-2b (1 MU/m² subcutaneously daily). Patients exhibiting a clinical response or stable disease after 12 weeks were treated until disease progression.

Results: Thirty-two patients (16 per arm) were accrued (18 male, 14 female; mean age 57.5 years). Both regimens were well tolerated. Six patients developed easily managed exacerbations of preexisting hypertension. Two patients developed grade 3 proteinuria that resolved after a treatment break. IFN-2b therapy was associated with grade 1 to 2 constitutional symptoms. Arterial thromboembolic complications were observed in three patients (two mild myocardial infarctions, one transient ischemic attack), all of whom had risk factors. One patient (Bev plus IFN-2b arm) had locally recurrent scalp disease that partially responded to therapy. Eight patients (five Bev, three Bev plus IFN-2b) had prolonged disease stabilization (24 to 146 weeks). Plasma levels of VEGF and FGF did not correlate with any clinical parameter. The patient with the longest period of stable disease had the highest baseline VEGF and FGF.

Conclusions: Bev was well tolerated at this dose and prolonged disease stabilization was achieved in one-quarter of metastatic melanoma patients. Low-dose IFN-2b did not augment the activity of Bev.

Key Words: Bevacizumab • Vascular endothelial growth factor (VEGF) • Angiogenesis • Interferon alfa-2b • Metastatic melanoma • Phase 2 clinical trial

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