title: Recombinant human tumor necrosis factor administered as a 24-hour intravenous infusion. A phase I and pharmacologic study.
abstract: 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.
authors.affiliation: Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute, Boston, MA 02115.
authors.forename: D R
authors.initials: DR
authors.lastname: Spriggs
authors.forename: M L
authors.initials: ML
authors.lastname: Sherman
authors.forename: H
authors.initials: H
authors.lastname: Michie
authors.forename: K A
authors.initials: KA
authors.lastname: Arthur
authors.forename: K
authors.initials: K
authors.lastname: Imamura
authors.forename: D
authors.initials: D
authors.lastname: Wilmore
authors.forename: E
authors.initials: E
authors.lastname: Frei
authors.forename: D W
authors.initials: DW
authors.lastname: Kufe
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004341:Drug Evaluation; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D007262:Infusions, Intravenous; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood
chemical_list: D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha