A phase I trial of bortezomib and interferon-α-2b in metastatic melanoma

Abstract

The possibility that cytokine administration could enhance the antitumor effects of proteasome inhibition was explored. It was found that coadministration 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 maximum tolerated dose of bortezomib when administered in combination with IFN-α-2b to patients with metastatic melanoma. Patients were treated on a 5-week cycle. In week 1 of cycle 1, patients received 5 million U/m(2) IFN-α subcutaneously thrice weekly. During weeks 2-4 of cycle 1, 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) to cohorts of 3 patients. Sixteen patients were treated (8 women, 8 men; median age 59 y). Common grade 3 toxicities included fatigue (5), vomiting (3), and diarrhea (3). Grade 4 toxicities included fatigue (3) and lymphopenia (1). The maximum tolerated dose 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 proangiogenic cytokines. The combination of bortezomib and IFN-α can be safely administered to melanoma patients.

Figure 1

Kaplan-Meier Survival curves. (A) Progression free survival with 95% confidence intervals (---). (B) Overall survival with 95% confidence intervals (---).

Figure 1

Kaplan-Meier Survival curves. (A) Progression free survival with 95% confidence intervals (---). (B) Overall survival with 95% confidence intervals (---).

Figure 2

A) A representative scatter plot of PBMCs obtained from peripheral blood. B) A histogram measuring pSTAT1 from a representative patient before and after treatment with interferon.

Figure 3

Levels of IL-8, IL-6, and VEGF in all patients. Patient plasma was collected prior to treatment and 1 hour after week 2 treatment with IFN-α-2B and bortezomib.