• Selection of the optimal dose of interferon alfa-2b (IFN-α-2b) using signal transduction data [ Designated as safety issue: Yes ]
  

• Tolerability of IFN-α-2b when administered at an optimized dose, in terms of toxicities observed and the ability of patients to receive a full year of therapy [ Designated as safety issue: Yes ]
  
• Correlation between STAT1 phosphorylation and IFN-α gene regulation as measured by real-time RT PCR [ Designated as safety issue: No ]
  
• Effect of dose reduction on IFN-α gene expression as measured by microarray analysis using peripheral blood mononuclear cell samples [ Designated as safety issue: No ]
  
• Clinical role of tumor sensitivity to IFN-α as measured by cellular levels of Jak-STAT signaling intermediates using tumor biopsy samples [ Designated as safety issue: No ]
  

OBJECTIVES:

Primary

• To determine whether selection of the optimal dose of interferon alfa-2b can be made using signal transduction data in patients who have undergone surgical resection for high-risk or metastatic melanoma.

Secondary

• To determine the tolerability of this drug when administered at an optimized dose, in terms of toxicities observed and the ability of patients to receive a full year of therapy.
• To determine the transcription of a panel of IFN-α-induced genes previously identified by microarray analysis using real-time RT PCR in order to evaluate the correlation between STAT1 phosphorylation and IFN-α gene regulation.
• To evaluate the effect of dose reduction on IFN-α gene expression by microarray analysis using peripheral blood mononuclear cell samples.
• To define the clinical role of tumor sensitivity to IFN-α by systematically evaluating cellular levels of Jak-STAT signaling intermediates using tumor biopsy samples.

OUTLINE: This is a dose-reduction study followed by a dose-optimization study.

Patients receive interferon alfa-2b (IFN-α-2b) IV 5 days a week for 4 weeks in the absence of disease progression or unacceptable toxicity. Patients then receive standard-dose IFN-α-2b subcutaneously (SC) 3 days a week for 1-2 months*. Patients who tolerate standard-dose IFN-α-2b then receive reduced doses of IFN-α-2b SC 3 days a week for up to 8 weeks. Once the optimized dose has been determined, patients receive IFN-α-2b at the optimized dose SC 3 days a week for up to 11 months** in the absence of disease progression or unacceptable toxicity.

NOTE: *The first 10 patients enrolled on the study receive standard-dose IFN-α-2b SC for 2 months. All subsequent patients receive standard-dose IFN-α-2b SC for 1 month.

NOTE: **Total treatment time with SC IFN-α-2b.

Blood samples are collected periodically during study treatment to obtain peripheral blood mononuclear cells (PBMCs) for correlative laboratory studies. Samples are analyzed for the presence of P-STAT1 and P-STAT2 within PBMCs, T cells, and NK cells by dual parameter flow cytometry. Levels of STAT1 and STAT2 (i.e., nonphosphorylated form) are measured to determine the degree of inter-patient variation and the effects of IFN-α on the expression of these species. Signal transduction is evaluated at each INF-α-2b dose level to determine whether a significant decrease in Jak-STAT activation has been achieved as a result of the dose reduction. PBMCs are also analyzed for induction of selected IFN-α-regulated genes by real-time RT PCR and for gene expression by microarray analysis.

Previously collected paraffin-embedded tumor tissue samples are analyzed for levels of Jak-STAT signaling intermediates by immunohistochemistry.

After completion of study therapy, patients are followed every 3-6 months for up to 2 years.