A Phase I Trial of Bortezomib and Interferon-alpha-2b in Metastatic Melanoma

作者：Markowitz Joseph; Luedke Eric A; Grignol Valerie P; Hade Erinn M; Paul Bonnie K; Mundy Bosse Bethany L; Brooks Taylor R; Thao Vi Dao; Kondalasula V; Lesinski Gregory B; Olencki Thomas; Kendra Kari L; Carson William E III^*

来源：Journal of Immunotherapy, 2014, 37(1): 55-62.

DOI：10.1097/CJI.0000000000000009

• bortezomib
• melanoma
• interferon
• phase I

The possibility that cytokine administration could enhance the antitumor effects of proteasome inhibition was explored. It was found that coadministration of bortezomib and interferon- (IFN-) 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--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- subcutaneously thrice weekly. During weeks 2-4 of cycle 1, bortezomib was administered intravenously weekly along with IFN- thrice weekly. There was a treatment break during week 5. After cycle 1, bortezomib was administered in combination with IFN-. Bortezomib was administered in escalating doses (1.0, 1.3, or 1.6 mg/m(2)) 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- 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- can be safely administered to melanoma patients.

• 出版日期2014-1