Journal of Clinical Oncology, Vol 6, 344-350, Copyright © 1988 by American Society of Clinical Oncology
Recombinant human tumor necrosis factor administered as a five-day continuous infusion in cancer patients: phase I toxicity and effects on lipid metabolism
ML Sherman, DR Spriggs, KA Arthur, K Imamura, E Frei 3d and DW Kufe
Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute, Boston, MA 02115.
Recombinant human tumor necrosis factor (rH-TNF) is a cytotoxic monokine
with pleiotropic effects. A phase I trial of rH-TNF was initiated using a
five-day continuous intravenous (IV) infusion repeated every 28 days.
Thirty-eight courses of therapy were administered to 19 patients. The
starting dose was 5 X 10(4) U/m2/d, with escalations to 1.0 X 10(5), 2.0 X
10(5), 2.4 X 10(5), and 3.0 X 10(5) U/m2/d. Systemic side effects,
including fever, chills, hypotension, fatigue, anorexia, and headaches,
were mild and self- limiting. At the maximum tolerated dose of 3.0 X 10(5)
U/m2/d, dose- limiting hematologic toxicity was manifested by transient
thrombocytopenia and leukopenia. Elevated bilirubin levels were also seen
at the higher dose levels. Lipoprotein analysis demonstrated that the
five-day treatment with rH-TNF was associated with decreases in
high-density lipoproteins, as well as increases in triglycerides and
very-low-density lipoproteins. Pharmacokinetic studies using an enzyme-
linked immunosorbent assay (ELISA) test indicated plasma rH-TNF levels less
than 0.2 U/mL. The recommended phase II dose of rH-TNF administered as a
five-day continuous infusion is 2.4 X 10(5) U/m2/d.
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