title: A phase I trial of intravenously-administered recombinant tumor necrosis factor-alpha in cancer patients.
abstract: We report a phase I clinical investigation of 30-minute and four-hour intravenous (IV) infusions of recombinant tumor necrosis factor (rTNF)-alpha. Thirty-nine patients with disseminated cancer received escalating doses of rTNF-alpha for five consecutive days every 2 weeks for a total duration of 8 weeks. Dose escalations followed a modified Fibonacci scale with a minimum of four patients entered at each dose level: 5, 10, 25, 50, 75, 100, 150, 200, and 250 micrograms/m2/d. Toxicities consisted mainly of constitutional symptoms including fever, chills, headache, and fatigue, increasing in severity with dose escalation. No significant differences in dose-limiting toxicities were seen between the two rates of IV infusion. The maximum tolerated dose (MTD) was 200 micrograms/m2 with dose limiting toxicity being constitutional symptoms and hypotension. Hematologic changes included median decrease in both granulocyte and platelet counts of 38% and 41%, respectively (range, 16% to 85%), although clinically significant granulocytopenia and thrombocytopenia were not observed. Hematological parameters returned to baseline within 72 hours after rTNF-alpha was stopped. rTNF-alpha induced changes in lipid metabolism were manifested by median fasting triglyceride elevations above baseline (median, 103 micrograms/dL) of 157% (range, 16% to 389%) after five days of therapy with doses greater than 75 micrograms/m2, associated with a median increase in very-low-density lipoprotein (VLDL) of 80%. Serum rTNF peak levels exceeding 10 ng/mL were observed 30 minutes following rTNF-alpha infusions at MTD dose. Twelve of 34 patients had no change in their evaluable disease for a median duration of 18 weeks (range, 8 to 30 weeks), and 22 patients showed progressive disease. This study forms the framework for phase II trials of IV administered rTNF-alpha.
authors.affiliation: Department of Clinical Immunology and Biological Therapy, University of Texas, M.D. Anderson Hospital and Tumor Institute, Houston 77030.
authors.forename: B
authors.initials: B
authors.lastname: Feinberg
authors.forename: R
authors.initials: R
authors.lastname: Kurzrock
authors.forename: M
authors.initials: M
authors.lastname: Talpaz
authors.forename: M
authors.initials: M
authors.lastname: Blick
authors.forename: S
authors.initials: S
authors.lastname: Saks
authors.forename: J U
authors.initials: JU
authors.lastname: Gutterman
mesh_terms: D000328:Adult; D000368:Aged; D000917:Antibody Formation; D001792:Blood Platelets / Q000187:drug effects; D004341:Drug Evaluation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000276:immunology
chemical_list: D014409:Tumor Necrosis Factor-alpha