A PHASE-I PHARMACOKINETIC STUDY OF RECOMBINANT HUMAN TUMOR-NECROSIS-FACTOR ADMINISTERED BY A 5-DAY CONTINUOUS INFUSION

Nineteen patients with advanced cancer were entered into a phase I clinical trial of Tumor Necrosis Factor (TNF) which was designed to determine the pharmacokinetic profile, safety, and maximal tolerated dose (MTD) of the recombinant human cytokine in vivo. TNF was administered by continuous infusion for 24 hours followed by pharmacokinetics and a 120-hour infusion repeated every 3 weeks. The initial dose was 40 mug/m2 and was ultimately escalated to 200 mug/m2. A total of forty 5-day cycles were administered to 18 of these patients; and all were evaluable for toxicity. Toxicities in this trial included fever, chills, rigors, hypotension, headaches, seizures, lethargy, weight loss, and malaise. At all dose levels, but more significantly at the highest doses, hematological toxicities were observed and grade 3 neurotoxicity (headache and confusion), and hypotension were noted. Two patients expired during the study, and this was felt to be related to septic episodes. Because of these severe toxicities, 160 mug/m2 was defined as the MTD. At 160 mug/m2 peak serum levels occurred within 5 - 20 minutes of initiation and were not detectable 1 hour later. No anti-tumor responses were observed. No measurable plasma levels of TNF were observed with the administration of doses of 80 mug/m2. This dose level could be further studied in phase II studies alone and in combination with other agents, utilizing a continuous infusion schedule.