CONCURRENT PHASE-I TRIALS OF INTRAVENOUS INTERLEUKIN-6 IN SOLID TUMORPATIENTS - REVERSIBLE DOSE-LIMITING NEUROLOGICAL TOXICITY

Interleukin 6 (IL-6) has antitumor activity comparable to IL-2 in muri ne models with less toxicity, Because the biological effects of interm ittent and continuous infusions may differ, we conducted two concurren t Phase I trials of daily x5, l-h, and continuous 120-h i,v, infusions to determine the toxicity, biological effects, and maximum tolerated dose of i,v, IL-6, Cohorts of six patients with advanced cancer receiv ed escalating doses (1, 3, 10, 30, 100, and 150 mu g/kg/day) of recomb inant human IL-6 on days 1-5 and 8-12 of each 28-day course (l-h trial ) or on days 1-5 of each 21-day course (120-h trial), Treatment was ad ministered in regular inpatient wards and in outpatient clinics and wa s withheld in the event of grade 3 toxicity, Sixty-nine patients (l-h trial, n = 40; 120-h trial, It = 29) were enrolled, including 27 with renal cancer and 16 with melanoma, All were ambulatory, and 30 were as ymptomatic, Fever (97%), anemia (78%), fatigue (56%), nausea or vomiti ng (49%), and elevated serum transaminase levels (42%) were the most f requent toxicities, Transient hypotension developed in 23 patients (33 %), There were three deaths during the study due to progressive diseas e and/or infection, There were no objective responses, Dose-related in creases in platelet counts and C-reactive protein levels were detected in most patients, Principal dose-limiting toxicities included atrial fibrillation (1 episode in the l-h trial and 4 episodes in the 120-h t rial) and neurological toxicities (3 episodes in the l-h trial and 4 e pisodes in the 120-h trial), The neurological toxicities included conf usion, slurred speech, blurred vision, proximal leg weakness, parapare sis, and ataxia, These effects were transient and reversed when IL-6 w as discontinued, IL-6 can be given by i,v, infusion at biologically ac tive doses with acceptable toxicity, Dose-limiting toxicities consiste d mainly of a spectrum of severe but transient neurological toxicities and occasional episodes of atrial fibrillation, The maximum tolerated doses recommended for use with these i,v, schedules in Phase II trial s are 100 mu g/kg/day by daily x5 l-h infusion and 30 mu g/kg/day by 1 20-h infusion, Phase II trials will be performed to determine the anti tumor activity of IL-6 and better define its toxicity, Patients in the se and other IL-6 studies should be monitored closely for neurological and cardiac effects.