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Margolin, K. et al.

Kim Margolin, Michael B. Atkins, Janice P. Dutcher, Marc S. Ernstoff, John W. Smith, Joseph I. Clark, Joseph Baar, Jeffrey Sosman, Jeffrey Weber, Chetan Lathia, Janice Brunetti, Frank Cihon, Brian Schwartz,

Phase I trial of BAY 50-4798, an interleukin-2-specific agonist in advanced melanoma and renal cancer.

PURPOSE: BAY 50-4798 is an analogue of interleukin-2 that selectively activates T cells over natural killer cells. This phase I study was designed to determine the maximum tolerated dose (MTD) and safety of BAY 50-4798, screen for tumor response, and assess pharmacokinetics. EXPERIMENTAL DESIGN: Forty-five patients with metastatic melanoma or renal cancer were enrolled, 31 on escalating doses to determine the MTD, with 20 renal cell carcinoma patients treated at MTD to detect antitumor activity. BAY 50-4798 was delivered i.v. every 8 h, days 1 to 5 and 15 to 19, and could be repeated after 9 weeks if tumor was stable or responding. RESULTS: The MTD was defined by and reported in terms of doses received. The doses tested ranged from 1.3 to 26.1 microg/kg, and the MTD was defined as 10.4 microg/kg based on toxicities similar to those of aldesleukin. Two patients achieved partial responses, one with melanoma and one with renal cell carcinoma. Among all 45 patients, 53% and 9% experienced a grade 3 and 4 toxicity, respectively. Among the patients treated at the MTD of 10.4 microg/kg, 71% and 10% experienced a grade 3 and 4 toxicity, respectively. Pharmacokinetics showed dose-dependent peak concentrations (C(max)) and area under the curve with a half-life of approximately 2 h and no evidence of accumulation. Lymphocyte subset analysis confirmed the preferential expansion of T-cell subsets over natural killer cells. CONCLUSIONS: The antitumor activity of BAY 50-4798 in malignancies that respond to high-dose interleukin-2 was low. BAY 50-4798 might provide advantages over aldesleukin in antigen-specific immunotherapies.[1]

References

Phase I trial of BAY 50-4798, an interleukin-2-specific agonist in advanced melanoma and renal cancer. Margolin, K., Atkins, M.B., Dutcher, J.P., Ernstoff, M.S., Smith, J.W., Clark, J.I., Baar, J., Sosman, J., Weber, J., Lathia, C., Brunetti, J., Cihon, F., Schwartz, B. Clin. Cancer Res. (2007) [Pubmed]

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