Clinical pharmacology of recombinant human tumor necrosis factor in patients with advanced cancer

P. B. Chapman, T. J. Lester, E. S. Casper, J. L. Gabrilove, G. Y. Wong, S. J. Kempin, P. J. Gold, S. Welt, R. S. Warren, H. F. Starnes, S. A. Sherwin, L. J. Old, H. F. Oettgen

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197 Scopus citations

Abstract

Twenty-six patients with advanced cancer refractory to standard therapy were treated with recombinant human tumor necrosis factor (rTNF) in a study aimed a determining the toxicity and tolerance of rTNF and at seeking evidence of antitumor activity. The study design involved two treatments per week for 4 weeks with alternating subcutaneous and intravenous (IV) administration, and weekly dose escalation through four levels in each patient. The dose range was 1 to 200 μg/m2 for IV bolus injection, and 5 to 250 μg/m2 for subcutaneous injection. Thirteen patients completed the full course. Early discontinuation of treatment was related to rTNF toxicity in seven cases. The major side effects were rigors, fever, headache, fatigue, and hypotension. Acute changes in granulocyte, lymphocyte, and monocyte counts, changes in serum zinc levels and plasma cortisol levels consistent with an acute phase response, and inflammation at the site of subcutaneous injection were also seen. At doses of 125 to 250 μg/m2, inflammation at the subcutaneous injection side was unacceptably severe. Minor changes were seen in hemostatic parameters. Hypotension was corrected by fluid administration and did not require treatment with vasopressors. Initial serum concentrations of rTNF were measured at five minutes after IV administration and were found to range from 2.5 ng/mL after a dose of 35 μg/m2 to 80 ng/mL after a dose of 200 μg/m2. The half-life of rTNF in the blood was 20 minutes. A decrease in lymph node size was observed in a patient with B cell lymphoma.

Original languageEnglish
Pages (from-to)1942-1951
Number of pages10
JournalJournal of Clinical Oncology
Volume5
Issue number12
DOIs
StatePublished - 1987
Externally publishedYes

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