Bortezomib and interferon alpha-2b in metastatic melanoma
| Autor: | Erinn M. Hade, Thomas Olencki, Sri Vidya Kondalasula, Valerie P. Grignol, William E. Carson, Bethany L. Mundy-Bosse, Bonnie Paul, Thao-Vi Dao, Gregory B. Lesinski, Eric Luedke, Joseph Markowitz, Kari Kendra |
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| Rok vydání: | 2013 |
| Předmět: | |
| Zdroj: | Journal of Clinical Oncology. 31:e20018-e20018 |
| ISSN: | 1527-7755 0732-183X |
| Popis: | e20018 Background: Preclinical studies revealed that bortezomib and interferon-α (IFN-α ) induce synergistic apoptosis in human melanoma cells. Combined treatment with bortezomib and IFN-α led to significant survival increases in a melanoma murine model. A phase I study is presented to determine the safety, tolerability and dose-limiting toxicity of bortezomib when administered in combination with interferon-alpha-2b (IFN-α) to patients with metastatic melanoma. Methods: Metastatic melanoma patients with ECOG status ≤ 2 were treated on a 5 week cycle. IFN-α (5 MU/m2) was administered subcutaneously (s.c.) on days 1, 3, and 5 of week one. During weeks 2-4 bortezomib was administered intravenously on day 1 along with IFNEα (5 MU/m2 s.c.) on days 1, 3, and 5. There was no treatment during week 5. After the first cycle, bortezomib was administered intravenously on day 1 of the weekly cycle along with IFNEα on days 1, 3, and 5. Bortezomib does levels were 1.0, 1.3, or 1.6 mg/m2 to cohorts of three patients. Results: 16 patients (8 men, 8 women, median age 58.5 (34-82) years) were treated. The most common metastatic disease sites included the lung, subcutaneous nodules, lymph nodes, and soft tissue. Other sites included: brain, skin, viscera, and bone. Grade 3 toxicities most frequently included fatigue, vomiting, and diarrhea. Syncope, depression, hypokalemia, motor neuropathy, and dyspnea were also observed. Grade 4 toxicities included fatigue and lymphopenia. There were 1 PR, 7 SD, and 8 PD. Median PFS and OS were 2.5 months (95% CI: 1.4-3.7) and 10.3 months (95% CI: 5.5-12.8), respectively. Bortezomib did not limit the ability of IFN-α to induce STAT1 phosphorylation in PBMCs. Levels of proEangiogenic cytokines (VEGF and IL-8) were higher in melanoma patients than in normal controls. Levels of VEGF, IL-8 and IL-6 all decreased during week 2 in the patient who experienced a PR. Bioplex cytokine analysis revealed decreases in IL-8 and VEGF in melanoma patients. Conclusions: Bortezomib and IFN-α represents a novel immune based treatment for melanoma. This combination reduces levels of pro-angiogenic factors in melanoma patients, is generally well tolerated, and can be safely administered to melanoma patients including those patients with treated CNS metastases. Clinical trial information: NCT01462773. |
| Databáze: | OpenAIRE |
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