Phase II trial of interleukin 1α and indomethacin in treatment of metastatic melanoma

John Edward Janik, L. L. Miller, D. L. Longo, G. C. Powers, W. J. Urba, W. C. Kopp, B. L. Gause, B. D. Curti, R. G. Fenton, J. J. Oppenheim, K. C. Conlon, J. T. Holmlund, M. Sznol, W. H. Sharfman, R. G. Steis, S. P. Creekmore, W. G. Alvord, A. E. Beauchamp, J. W. Smith

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Abstract

Background: The rising incidence of malignant melanoma and the lack of curative therapies for metastatic disease represent a therapeutic challenge. New agents effective in treating this disease are needed. Purpose: Because of the additive antitumor effects of interleukin 1α (IL-1α) and indomethacin in vivo, we conducted a phase II trial of this combination in patients with melanoma. We used the recommended dose determined from our phase l trial to ascertain the antitumor activity of the combination. Methods: From August 1, 1990, through July 28, 1992, 49 patients entered the study. They were stratified into two groups based on the presence of visceral (n = 14) and nonvisceral (n = 35) metastases. The patients received 7 days of both IL-1α (0.1 μg/kg per day by intravenous bolus infusion) and indomethacin (50 mg orally every 8 hours). At least two cycles of therapy, repeated at 21-day intervals, were planned. Additional treatment was given to those patients who had stable or responding lesions. A chi-squared test for homogeneity of proportions was used to compare groups on several measures. All P values resulted from two-sided tests. Results: Fever, chills, and hypotension were among the most common side effects. None of the 14 patients with visceral metastases responded to the treatment. Of the 35 patients with nonvisceral metastases, three showed a partial response for 6 months each and one showed a complete response for more than 34 months; the response rate was 11% (95% confidence interval [CI] = 5%-26%). All responding patients required phenylephrine for treatment of IL-1α-induced hypotension, whereas six (19%) of 31 of the nonresponding patients with nonvisceral metastases required phenylephrine (P = .0008). The response rate in women was higher; three of 10 women (30%; 95% CI = 11%-60%) responded, whereas one of 25 men (4%; 95% CI = 0%-20%) responded (P = .029). All three women were positive for human leukocyte antigen (HLA) B7 expression (P = .011). Conclusions: The combination of IL-1α and indomethacin has minimal antitumor activity in melanoma patients. All responses were confined to patients with nonvisceral metastases. IL-1α-induced hypotension, gender, and HLA B7 expression were positively associated with response. Implications: Administration of higher doses of IL-1α alone has been shown to produce hypotension in a large proportion of patients but can be given safely with phenylephrine support. Because of the association of hypotension with antitumor activity, treatment with higher IL-1α doses alone may be a strategy for attaining better response rates.

Original languageEnglish (US)
Pages (from-to)44-49
Number of pages6
JournalJournal of the National Cancer Institute
Volume88
Issue number1
DOIs
StatePublished - Jan 12 1996

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Janik, J. E., Miller, L. L., Longo, D. L., Powers, G. C., Urba, W. J., Kopp, W. C., Gause, B. L., Curti, B. D., Fenton, R. G., Oppenheim, J. J., Conlon, K. C., Holmlund, J. T., Sznol, M., Sharfman, W. H., Steis, R. G., Creekmore, S. P., Alvord, W. G., Beauchamp, A. E., & Smith, J. W. (1996). Phase II trial of interleukin 1α and indomethacin in treatment of metastatic melanoma. Journal of the National Cancer Institute, 88(1), 44-49. https://doi.org/10.1093/jnci/88.1.44