title: Phase II trial of interleukin 1 alpha and indomethacin in treatment of metastatic melanoma.
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.
  
  
  OBJECTIVE
  Because of the additive antitumor effects of interleukin 1 alpha (IL-1 alpha) 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-1 alpha (O.1 micrograms/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 non-visceral 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-1 alpha-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-1 alpha and indomethacin has minimal antitumor activity in melanoma patients. All responses were confined to patients with nonvisceral metastases. IL-1 alpha-induced hypotension, gender, and HLA B7 expression were positively associated with response.
  
  
  CONCLUSIONS
  Administration of higher doses of IL-1 alpha 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-1 alpha doses alone may be a strategy for attaining better response rates.
authors.affiliation: Biological Response Modifiers Program, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21701-4507, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Janik
authors.forename: L L
authors.initials: LL
authors.lastname: Miller
authors.forename: D L
authors.initials: DL
authors.lastname: Longo
authors.forename: G C
authors.initials: GC
authors.lastname: Powers
authors.forename: W J
authors.initials: WJ
authors.lastname: Urba
authors.forename: W C
authors.initials: WC
authors.lastname: Kopp
authors.forename: B L
authors.initials: BL
authors.lastname: Gause
authors.forename: B D
authors.initials: BD
authors.lastname: Curti
authors.forename: R G
authors.initials: RG
authors.lastname: Fenton
authors.forename: J J
authors.initials: JJ
authors.lastname: Oppenheim
authors.forename: K C
authors.initials: KC
authors.lastname: Conlon
authors.forename: J T
authors.initials: JT
authors.lastname: Holmlund
authors.forename: M
authors.initials: M
authors.lastname: Sznol
authors.forename: W H
authors.initials: WH
authors.lastname: Sharfman
authors.forename: R G
authors.initials: RG
authors.lastname: Steis
authors.forename: S P
authors.initials: SP
authors.lastname: Creekmore
authors.forename: W G
authors.initials: WG
authors.lastname: Alvord
authors.forename: A E
authors.initials: AE
authors.lastname: Beauchamp
authors.forename: J W
authors.initials: JW
authors.lastname: Smith
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016009:Chi-Square Distribution; D005260:Female; D015235:HLA-B Antigens / Q000097:blood; D006801:Humans; D007213:Indomethacin / Q000008:administration & dosage; D007375:Interleukin-1 / Q000008:administration & dosage; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D008875:Middle Aged; D012737:Sex Factors; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D015235:HLA-B Antigens; D007375:Interleukin-1; D007213:Indomethacin