PHASE IB EVALUATION OF IL-1 BETA

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Interleukin-1 beta (IL-1Beta) possesses antiproliferative, immunostimulatory, anti-infection, myeloprotective, and myelorestorative properties that could be beneficial in cancer treatment. In this phase I trial, IL-1Beta was administered IV over 15 minutes daily for seven days to patients with advanced solid malignancies. The maximum tolerated dose of IL-1beta alone was 0.3 mcg/kg. A second group of patients received indomethacin plus IL-1Beta based on pre-clinical studies indicating that indomethacin could abrogate IL-1Beta-induced hypotension. The MTD of IL-1Beta plus indomethacin has not been determined, although one patient has had dose-limiting toxicity at 0.3 mcg/kg plus indomethacin. Fever, chills, headache, nausea, vomiting, and myalgia were commonly observed, but were not dose-limiting. Hypotension requiring IV fluids and pressors was observed at doses of 0.1 mcg/kg and above. Dose-limiting toxicities were grade IV hypotension, bronchospasm, myocardial ischemia, and atrial and ventricular arrhythmias. IL-1Beta treatment caused a significant dose-related increase in the total white blood count (mainly segmented neutrophils and neutrophilic bands). Bone marrow cellularity was increased after three days and seven days of treatment. Platelet counts declined during therapy, but were significantly elevated above baseline 1-2 weeks after the end of treatment. Significant increases in G-CSF and IL-6 were noted and may have been responsible for the observed hematopoietic effects. Pharmacokinetic studies indicated IL-1Beta to have a short half-life of 10-15 minutes. This study demonstrates that IL-1Beta can be safely administered to humans, that it produces biological effects very similar to those observed with IL-1Alpha, and that important, potentially beneficial, hematopoietic effects occur at well-tolerated doses of IL-1Beta.