A phase I clinical trial of recombinant human tumor necrosis factor.
We performed a Phase I assessment of recombinant human tumor necrosis factor (rTNF-alpha) in 27 patients with advanced solid neoplasms. Therapy consisted of a 30-minute intravenous (IV) infusion on days 1 through 5, every 2 to 3 weeks. Daily doses ranged from 5 micrograms/m2 to 200 micrograms/m2. Dose-limiting sequelae were hypotension, rigors, and phlebitis. Transient fatigue and fever (median, 38 degrees C) were not clearly dose-related between 5 micrograms/m2/d and 150 micrograms/m2/d. Other reversible complications in three patients included transient leukopenia (leukocyte count, 1.3, 1.2 X 10(3)/microliters in two patients) at a dose of 5 micrograms/m2/d and 150 micrograms/m2/d, respectively; and thrombocytopenia (leukocyte count, 73 X 10(3)/microliters) at 10 micrograms/m2/d. Among 22 patients with initial and subsequent differential counts, the median number of eosinophils at the commencement of therapy was 182 cells/microliters compared with a subsequent median of 462 cells/microliters. We also detected hypertriglyceridemia in all patients. The median baseline increased from 93 mg/dl (range, 56 to 219 mg/dl) to 203 mg/dl (range, 94 to 454 mg/dl). From our experience, a clinically manageable outpatient regimen for Phase II trials consists of rTNF-alpha (150 micrograms/m2) followed by a 1-hour IV infusion of 500 ml of normal saline to abrogate hypotension daily for 5 days every 2 weeks for four cycles, then every 3 weeks thereafter to facilitate recovery from constitutional sequelae.
Creagan
E T
ET
Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905.
Kovach
J S
JS
Moertel
C G
CG
Frytak
S
S
Kvols
L K
LK
D000328:Adult; D000368:Aged; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D015228:Hypertriglyceridemia / Q000139:chemically induced; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D013921:Thrombocytopenia / Q000139:chemically induced; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000627:therapeutic use*
D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha