A phase I trial of subcutaneously administered recombination tumor necrosis factor to patients with advanced malignancy.

Nineteen patients with advanced cancer for which there was no effective standard therapy or whose disease was refractory to standard therapy were treated with recombinant tumor necrosis factor (rTNF). The rTNF was administered subcutaneously for 5 consecutive days every other week for 3 treatment weeks. The doses administered ranged from 5 micrograms/m2/day to 150 micrograms/m2/day. There was no intrapatient dose escalation. Systemic side effects of chills, fever, hypotension, nausea, vomiting, and headache were mild and self-limiting. At the maximum tolerated dose of 150 micrograms/m2/day, five of seven patients experienced moderate to severe thrombocytopenia. Mild rapid declines in total leukocyte count occurred within 60-90 min of administration of the drug, followed by a rise in the total leukocyte count by 120 min. When the total daily dose was administered in a single subcutaneous site, skin ulceration and necrosis occurred at the 100 micrograms/m2/day dose. By giving the total daily dose in two subcutaneous sites, the maximum tolerated dose increased to 150 micrograms/m2/day, and there was no further skin ulceration or necrosis. Skin necrosis occurred in the abdomen and thigh but not on the upper extremity at the 100 micrograms/m2/day dose given in a single site. There was no other significant organ toxicity. No rTNF was detectable in the serum even at the highest doses. No antibodies to TNF developed in any of the patients. The recommended dose of rTNF for Phase II trials given for 5 days subcutaneously is 150 micrograms/m2/day divided into two or more sites.