A Phase 2 Trial of Bevacizumab and High-dose Interferon Alpha 2B in Metastatic Melanoma

Abstract

Bevacizumab is a humanized recombinant monoclonal antibody that neutralizes vascular endothelial growth factor, an agent with pro-angiogenic effects in melanoma. Interferon-alpha (IFN-α) has anti-angiogenic properties via its ability to down-regulate basic-fibroblast growth factor levels. We hypothesized that the co-administration of these agents would lead to tumor regression. Patients with metastatic melanoma received bevacizumab 15 mg/kg iv on day 1 of the 2 week cycle. IFN-α was administered thrice weekly at 5 MU/m2 sc during cycle 1 and was increased to 10 MU/m2 during cycle 2. Patients were restaged every 6 cycles. Patients with stable disease or a response continued with therapy. Baseline serum VEGF and FGF were measured. Twenty-five patients were accrued. Mean age was 58.4 years. Eleven patients required IFN-α dose reductions due to toxicity. Common grade 3 toxicities associated with IFN-α included fatigue and myalgia. Bevacizumab administration was associated with grade 2–3 proteinuria in 6 patients. Grade 4 adverse events were pulmonary embolus (1), myocardial infarction (1), and stroke (1). Six patients had a partial response, and five patients exhibited stable disease that lasted greater than 24 weeks (range 30–122 weeks). Median PFS and OS were 4.8 months and 17 months, respectively. Significantly lower FGF levels were observed in patients with a partial response compared to those with stable or progressive disease (p=0.040). Administration of bevacizumab with IFN led to a clinical response in 24% of patients with stage IV melanoma and stabilization of disease in another 20% of patients. This regimen has activity in advanced melanoma.

Metastatic Melanoma: Lactate Dehydrogenase Levels and CT Imaging Findings of Tumor Devascularization Allow Accurate Prediction of Survival in Patients Treated with Bevacizumab

“…Patients with metastatic melanoma who were treated with bevacizumab with or without interferon α2b were included as part of a randomized phase II prospective clinical trial. The trial was initiated at the Ohio State University Comprehensive Cancer Center in December 2001 and extended through April 2012 (5,7). The first two treatment arms of the randomized phase II trial consisted of patients who received bevacizumab with or without very low-dose interferon α2b (1 MU/m 2 ).…”

“…Patients included ( n = 62) in the trial were those who had histologically confirmed malignant melanoma; were aged 18 years or older; had a life expectancy of 6 months or more, an Eastern Cooperative Oncology Group status less than or equal to 1, normal organ function, pretherapy CT imaging less than or equal to 90 days before the start of therapy, and initial posttherapy CT imaging 21–120 days after the start of therapy. The specific aim of the clinical trial was to evaluate progression-free survival and the objective response rate to bevacizumab when it is used in combination with interferon α2b for treatment of metastatic melanoma (5,7). Patients for whom baseline and initial posttherapy CT imaging ( n = 13) were unavailable and those who had insufficient clinical and laboratory data ( n = 3) or had undergone pretherapy CT imaging more than 90 days from the start of therapy ( n = 2) were excluded.…”

“…Bevacizumab combined with high-dose interferon α2b has been shown to decrease tumor size in a substantial proportion of patients with metastatic melanoma (5). …”

The use of interferon in melanoma patients: A systematic review

“…The newer agents (vemurafenib, ipilimumab, dabrafenib, trametinib) are the first to show improved OS in phase III studies in comparison with other systemic therapies. Recently, phase II trials have showed that combinations of IFN-a or PEG-IFN with other agents (sorafenib, bevacizumab, tremelimumab, immunotherapy) has potential clinical efficacy in stage IV melanoma patients and appears to have an acceptable safety profile, although no conclusive evidence of the efficacy of these combinations is yet available [71][72][73][74][75].…”

Chinese Guidelines on the Diagnosis and Treatment of Melanoma (2015 Edition)

“…Bevacizumab is a monoclonal antibody that can selectively bind VEGF and block its binding with receptors. It has been widely applied in the treatment of metastatic melanoma (182)(183)(184)(185). In a randomized, double-blind phase II study (BEAM study), 214 metastatic melanoma patients were randomized into carboplatin + paclitaxel + bevacizumab (CPB) group or placebo group (CP) at a proportion of 2:1.…”