title: Randomized placebo-controlled clinical trial of high-dose interleukin-2 in combination with a soluble p75 tumor necrosis factor receptor immunoglobulin G chimera in patients with advanced melanoma and renal cell carcinoma.
abstract: OBJECTIVE
  A randomized, double-blind, placebo-controlled trial was performed to compare the toxicity and biologic effects of treatment with high-dose intravenous (IV) bolus interleukin-2 (IL-2) plus the recombinant human soluble p75 tumor necrosis factor (TNF) receptor immunoglobulin G (IgG) chimera (rhuTNFR:Fc) with high-dose IL-2 alone in patients with advanced melanoma and renal cell carcinoma.
  
  
  METHODS
  Twenty patients with advanced melanoma or renal cell carcinoma were randomized to receive IL-2 (Chiron, Emeryville, CA) 600,000 IU/kg every 8 hours on days 1 to 5 and 15 to 19 (maximum, 28 doses) combined with placebo or the rhuTNFR:Fc fusion protein (Immunex, Seattle, WA) 10 mg/m2 on days 1 and 15 and 5 mg/m2 on days 3, 5, 17, and 19. The impact of rhuTNFR:Fc on IL-2 toxicity and biologic effects was evaluated.
  
  
  RESULTS
  No clinically significant difference in toxicity was observed in the two treatment arms. The adjusted median number of IL-2 doses administered during cycle 1 was 24.5 (range, seven to 28) and 21.5 (range, five to 27) for the placebo and rhuTNFR:Fc arms, respectively (P = .544). IL-2-induced TNF bioactivity, neutrophil chemotactic defect, and serum IL-6, IL-8, and IL-1 receptor antagonist (IL-1RA) induction were suppressed by rhuTNFR:Fc. Two of nine assessable patients (22%) on IL-2/placebo and three of 10 patients (30%) on IL-2/rhuTNFR:Fc responded.
  
  
  CONCLUSIONS
  Despite evidence of in vitro neutralization of TNF functional activity and partial inhibition of other secondary biologic effects of IL-2, rhuTNFR:Fc does not reduce the clinical toxicity associated with high-dose IL-2 therapy. These results suggest that the toxicity and antitumor effects of IL-2 treatment are independent of circulating TNF.
authors.affiliation: Biologic Therapy Program, Tufts University School of Medicine and New England Medical Center Hospitals, Boston, MA 02111, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Du Bois
authors.forename: E G
authors.initials: EG
authors.lastname: Trehu
authors.forename: J W
authors.initials: JW
authors.lastname: Mier
authors.forename: L
authors.initials: L
authors.lastname: Shapiro
authors.forename: M
authors.initials: M
authors.lastname: Epstein
authors.forename: M
authors.initials: M
authors.lastname: Klempner
authors.forename: C
authors.initials: C
authors.lastname: Dinarello
authors.forename: K
authors.initials: K
authors.lastname: Kappler
authors.forename: L
authors.initials: L
authors.lastname: Ronayne
authors.forename: W
authors.initials: W
authors.lastname: Rand
authors.forename: M B
authors.initials: MB
authors.lastname: Atkins
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D016130:Immunophenotyping; D007376:Interleukin-2 / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009000:Monocytes; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology
chemical_list: D015703:Antigens, CD; D007074:Immunoglobulin G; D007376:Interleukin-2; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins