Recombinant Human Tumor Necrosis Factor Administered as a 24-Hour Intravenous Infusion. A Phase I and Pharmacologic Study

Abstract

Recombinant human tumor necrosisj factor (rH-TNF) is a cytokine with direct antitumor properties. In a phase I trial we continuously infused rH-TNF for 24 hours. We gave a total of 115 courses of therapy to 50 patients. Doses ranged from 4.5 to 645 μg of rH-TNF/m². Systemic toxicity, including fever, chills, fatigue, and hypotension, increased with the does of rH-TNF administered. Doses >454 μg/m² frequently caused severe lethargy and fatigue, which precluded hospital discharge of the patient at the completion of therapy. The dose-limiting toxicity was gypotension, and five patients treated at the two high3est dose levels requirede dopamine treatment. Other organ-specific toxicity was modest and spontaneously resolved after 48hours. The24-hour infusions of rH-TNF were associated weith significant decreases in serum cholesterol and high-density lipoprotein levels. Pharmacokinetic studies using an enzyme-linked immunosorbent assay demonstrated peak plasma rH-TNF levels of 90-900 pg/mL. Despite continuous infusion of rH-TNF. no steady-state level was achieved. The recommended phase II dose for rH-TNF as a 24-hour continuous infusion is 545 μg/m². [Natl Cancer Inst 1988;80:1039–1044]