PHASE I EVALUATION OF INTERLEUKIN-1 ALPHA

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Interleukin-1 alpha (IL-1Alpha) possesses antiproliferative, immunostimulatory, anti-infection, myeloprotective, and myelorestorative properties that could be beneficial in cancer treatment. In this phase I trial, IL-1Alpha was administered IV over 15 minutes daily for 7 days to patients with advanced solid malignancies. The maximum tolerated dose (MTD) of IL-1Alpha alone was 0.3 Micro g/kg. A second group of patients received indomethacin plus IL-1Alpha based on preclinical studies indicating that indomethacin could abrogate IL-1Alpha-induced hypotension; however, the maximum tolerated dose of IL-1Alpha plus indomethacin, 0.1 Micro g/kg, was lower than IL-1Alpha alone. Fever, chills, headache, nausea, vomiting, and myalgia were commonly observed but were not dose-limiting. Hypotension resulted from a marked decrease in systemic vascular resistance and required pressors at 0.3 and 1.0 Micro g/kg IL-1Alpha. Dose-limiting toxicities included hypotension, myocardial infarction, confusion, and renal insufficiency. IL-1Alpha treatment caused a significant, dose-related increase in total white blood count (mainly segmented neutrophils and neutrophilic bands). Bone marrow cellularity increased due to enhanced numbers of relatively mature myeloid cells and megakaryocytes. Platelet counts declined during therapy but were significantly elevated above baseline 1-2 weeks after the end of treatment; this may have been due to IL-6 that was shown to be induced by IL-1Alpha treatment. Significant increases in triglycerides, cortisol, C-reactive protein, thyroid stimulating hormone and decreases in cholesterol, testosterone and protein-C were observed with treatment. Pharmacokinetic studies indicated IL-1Alpha to have a short half-life of 10-15 minutes. We conclude that at doses of IL-1Alpha that can be safely given to cancer patients, significant, potentially beneficial hematopoietic effects occur.