A phase I study withrecombinant human tumor necrosis factor a (rhuTNF-a; Knoll AG, Ludwigshafen, FRG) in patients with advanced malignant disease was undertaken to evaluate drug toxicity (organ specifity, time course, predictability, reversibility, maximal tolerated dose), effectiveness, antigenicity and pharmacokinetics. T N F was administered as a test dose followed by daily i.v. infusions for 5 days, every 3 weeks (single i.v. infusion lasting 10 min, TNF dissolved in 50 ml 5% human albumin). Dosage was increased in groups of 3 or 4 patients from 0.04 m g / m 2 to 0.28 m g / m 2. A total of19 patients with different cancers, including seven large-bowel carcinomas, three chronic myelogenous leukemias, three hypernephromas, two small-cell lung cancers, one malignant melanoma, one malignant lymphoma, one rhabdomyosarcoma and one fibrosarcoma were treated. Major side-effects were chills and fever (maximum 40.4 ° C, median 38.7 ° C, 19/19), headache (12/19), nausea and vomiting (12/19) and pronounced (> 20%) hypotension (4/19). Acute sideeffects could be diminished by paracetamol or indomethacin pretreatment, and with one possible exception no tachyphylaxis to TNF was noted. Mild renal toxicity was seen during TNF treatment. Pharmacokinetic studies showed a serum half-life (tl/2) ranging from 11 min to 17 min for doses from 0.04 m g / m 2 to 0.16 m g / m 2 and prolonged clearance with tl/2 ranging from 54 min to 70 min in the 0.20-0.28 m g / m 2 dose range. No objective antitumor effects were observed in this phase I study.