PHASE-I TRIAL OF INTERLEUKIN-2 IN COMBINATION WITH THE SOLUBLE TUMOR-NECROSIS-FACTOR RECEPTOR P75 IGG CHIMERA

Our purpose was to determine the effective biological dose and/or maxi mum tolerated dose of recombinant human tumor necrosis factor receptor :IgG chimera (rhuTNFR:Fc; Immunex, Seattle, WA) in combination with in terleukin 2 (IL-2) with regard to reduction in IL-2 toxicity and modul ation of biological effects of high-dose IL-2 administration, Twenty-f our patients with metastatic cancer were treated with escalating doses of rhuTNFR:Fc at 1, 1, 5, 10, and 20 mg/m(2) i,v, on days 1 and 15 (d ose levels 1-5) or 10, 20, and 30 mg/m(2) days 1 and 15 plus 50% dose on days 3, 5, 17, and 19 (dose levels 6-8) prior to IL 2 at doses of 3 00,000 IU/kg (dose level 1) and 600,000 IU/kg (dose levels 2-8) i,v, e very 8 h on days 1-5 and 15-19, The t(1/2) of rhuTNFR in patients rece iving IL-2 was 72 h, The median number of IL-2 doses was 24, and centr al nervous system, skin, and cardiac arrhythmias were the major dose-l imiting toxicities. TNF bioactivity was inhibited, and the polymorphon uclear leukocyte chemotactic defect normally seen with IL-2 was not ob served, Increases in C-reactive protein, IL-6, IL-8, and IL-1 receptor antagonist levels were partially suppressed relative to historical co ntrols, whereas peripheral blood mononuclear cell phenotypes, urinary nitrate, endothelial adhesion molecule expression in skin biopsies, an d cellular infiltrates in tumor biopsies were consistent with findings in patients treated with IL-2 alone, Four patients developed thyroid dysfunction, There were five responses: two complete responses (both m elanoma) and three partial responses (response rate, 21%), rhuTNFR:Fc may modulate the toxicity and some of the biological effects of IL-2 w hile preserving antitumor activity, Dose level 6 (10 mg/m(2) on days 1 and 15, and 5 mg/m(2) on days 3, 5, 17, and 19) has been chosen for a randomized, double-blind, placebo-controlled trial of IL-2 with and w ithout rhuTNFR:Fc.