Recombinant human tumor necrosis factor administered as a 24-hour intravenous infusion. A phase I and pharmacologic study

Recombinant human tumor necrosis 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 micrograms of rH-TNF/m2. Systemic toxicity, includin...

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Published inJNCI : Journal of the National Cancer Institute Vol. 80; no. 13; p. 1039
Main Authors Spriggs, D R, Sherman, M L, Michie, H, Arthur, K A, Imamura, K, Wilmore, D, Frei, 3rd, E, Kufe, D W
Format Journal Article
LanguageEnglish
Published United States 07.09.1988
Subjects
Adolescent
Adult
Aged
Drug Evaluation
Humans
Hypotension - chemically induced
Infusions, Intravenous
Middle Aged
Neoplasms - therapy
Recombinant Proteins - administration & dosage
Recombinant Proteins - adverse effects
Recombinant Proteins - blood
Tumor Necrosis Factor-alpha - administration & dosage
Tumor Necrosis Factor-alpha - adverse effects
Tumor Necrosis Factor-alpha - blood
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Summary:Recombinant human tumor necrosis 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 micrograms of rH-TNF/m2. Systemic toxicity, including fever, chills, fatigue, and hypotension, increased with the dose of rH-TNF administered. Doses greater than 454 micrograms/m2 frequently caused severe lethargy and fatigue, which precluded hospital discharge of the patient at the completion of therapy. The dose-limiting toxicity was hypotension, and five patients treated at the two highest dose levels required dopamine treatment. Other organ-specific toxicity was modest and spontaneously resolved after 48 hours. The 24-hour infusions of rH-TNF were associated with 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 micrograms/m2.
ISSN:0027-8874
DOI:10.1093/jnci/80.13.1039