A Phase I trial of Bortezomib and Interferon Alfa-2B in Metastatic Melanoma

The possibility that cytokine administration could enhance the anti-tumor effects of proteasome inhibition was explored. It was found that co-administration of bortezomib and interferon-α (IFN-α) induced synergistic apoptosis in human melanoma cell lines and prolonged survival in a murine model of melanoma. A phase I study was conducted to determine the tolerability and the maximally tolerated dose (MTD) of bortezomib when administered in combination with interferon-α-2b to patients with metastatic melanoma. Patients were treated on a 5 week cycle. In week 1 of cycle 1 patients received 5 MU/m 2 IFN-α subcutaneously thrice weekly. During weeks 2–4 of cycle one bortezomib was administered intravenously weekly along with IFN-α thrice weekly. There was a treatment break during week 5. After cycle 1, bortezomib was administered in combination with IFN-α. Bortezomib was administered in escalating doses (1.0, 1.3, or 1.6 mg/m 2 ) to cohorts of three patients. 16 patients were treated (8 female, 8 male; median age 59 years). Common grade 3 toxicities included fatigue (5), vomiting (3), and diarrhea (3). Grade 4 toxicities included fatigue (3) and lymphopenia (1). The MTD for bortezomib was 1.3 mg/m 2 . One patient had a partial response and 7 had stable disease. Progression-free survival was 2.5 months and overall survival was 10.3 months. Bortezomib administration did not augment the ability of IFN-α to induce phosphorylation of STAT1 in circulating immune cells; however, it did lead to reduced plasma levels of pro-angiogenic cytokines. The combination of bortezomib and IFN-α can be safely administered to melanoma patients.