Phase I evaluation of thrice-daily intravenous bolus interleukin-4 in patients with refractory malignancy.

PURPOSE: A phase I dose-escalation trial of recombinant human interleukin-4 (IL-4) was performed to determine its toxicity, biologic activity, and potential antineoplastic effects. PATIENTS AND METHODS: Ten patients with refractory malignancies received IL-4 by bolus intravenous injection every 8 hours on days 1 to 5 and 15 to 19 (maximum, 28 doses) of a 31-day study period. Three patients received 10 micrograms/kg per dose and seven received 15 micrograms/kg per dose of IL-4. RESULTS: Toxic symptoms noted at the second dose level included nasal congestion, diarrhea, nausea and vomiting, fatigue, anorexia, headache, dyspnea, and capillary leak syndrome (median weight gain, 6.1%; range, 3.4% to 11.7%). Fever or sustained hypotension sufficient to require pressors did not occur. Decreases in lymphocyte count and serum bicarbonate, sodium, albumin, fibrinogen and immunoglobulin (Ig) levels, and increases in hematocrit, prothrombin time/partial thromboplastin time (PT/PTT), soluble CD23, and, occasionally, serum creatinine and transaminases occurred. All side effects resolved by day 31. Phenotypic analysis of peripheral-blood mononuclear cells (PBMC) showed a decrease in the percentage of circulating CD16 and CD14(+) cells. Plasma tumor necrosis factor (TNF) and IL-1 beta levels were unaffected, whereas serum C-reactive protein (CRP) concentrations increased slightly and plasma IL-1 receptor antagonist (IL-1RA) levels increased markedly. No tumor responses were observed. CONCLUSIONS: We conclude that 10 micrograms/kg per dose of IL-4 is the maximum-tolerated dose for this schedule, although 15 micrograms/kg per dose can be tolerated if more intensive, but still non-intensive care unit level care is provided. The results of this study should aid in the design of future phase II trials that involve IL-4 alone or phase I studies that combine IL-4 with other cytokines such as IL-2.