Journal of Clinical Oncology, Vol 15, 1052-1062, Copyright © 1997 by American Society of Clinical Oncology
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
JS Du Bois, EG Trehu, JW Mier, L Shapiro, M Epstein, M Klempner, C Dinarello, K Kappler, L Ronayne, W Rand and MB Atkins
Biologic Therapy Program, Tufts University School of Medicine and New England Medical Center Hospitals, Boston, MA 02111, USA.
PURPOSE: 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. PATIENTS AND 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. CONCLUSION: 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.
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