Phase II Trial of Interleukin 1α and Indomethacin in Treatment of Metastatic Melanoma

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 I 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 (0.1μg/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 antitum