Phase I trial of recombinant human tumour necrosis factor alpha in patients with advanced malignancy.
A phase I clinical trial was conducted with recombinant human tumour necrosis factor alpha (rhTNF-alpha) in 62 patients with advanced malignancy refractory to previous standard therapy. rhTNF-alpha was given as a 30 min infusion twice a day at 6 h intervals. A total of 10 different dose levels was escalated in cohorts of 6 patients ranging from 2.5 to 200 micrograms/m2 twice a day for 5 days every second week for a total of 8 weeks followed by a 4-week observation period. Major side-effects of TNF-alpha therapy, seen in almost all patients studied, were fever and chills. As dose-limiting side-effects hypotension and liver toxicity were recorded in 4 of 5 patients treated with 200 micrograms/m2 twice a day. Pharmacokinetic studies revealed a TNF-alpha serum half-life of 13 to 25 min, a dose-dependent decrease in TNF clearance, and a dose-dependent increase in the area under the time/concentration curve. No anti-TNF-alpha antibodies could be detected, except in 1 patient. Tumour response to TNF treatment was poor. Only in 3 of 57 evaluable patients was partial tumour regression observed.
Gamm
H
H
Department of Hematology and Oncology, University of Freiburg Medical Center, Germany.
Lindemann
A
A
Mertelsmann
R
R
Herrmann
F
F
D000293:Adolescent; D000328:Adult; D000368:Aged; D001792:Blood Platelets / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005260:Female; D005334:Fever / Q000139:chemically induced; D006454:Hemoglobins / Q000187:drug effects; D006801:Humans; D007958:Leukocyte Count / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010976:Platelet Count / Q000187:drug effects; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D006454:Hemoglobins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha