A phase I clinical trial of recombinant human tumor necrosis factor given daily for five days

Recombinant human tumor necrosis factor (rH-TNF) is a cytotoxic monokine with pleiotropic effects. A phase I trial of rH-TNF was initiated using a five-day continuous intravenous (IV) infusion repeated every 28 days. Thirty-eight courses of therapy were administered to 19 patients. The starting dose was 5 X 10(4) U/m2/d, with escalations to 1.0 X 10(5), 2.0 X 10(5), 2.4 X 10(5), and 3.0 X 10(5) U/m2/d. Systemic side effects, including fever, chills, hypotension, fatigue, anorexia, and headaches, were mild and self-limiting. At the maximum tolerated dose of 3.0 X 10(5) U/m2/d, dose-limiting hematologic toxicity was manifested by transient thrombocytopenia and leukopenia. Elevated bilirubin levels were also seen at the higher dose levels. Lipoprotein analysis demonstrated that the five-day treatment with rH-TNF was associated with decreases in high-density lipoproteins, as well as increases in triglycerides and very-low-density lipoproteins. Pharmacokinetic studies using an enzyme-linked immunosorbent assay (ELISA) test indicated plasma rH-TNF levels less than 0.2 U/mL. The recommended phase II dose of rH-TNF administered as a five-day continuous infusion is 2.4 X 10(5) U/m2/d.

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Phase I clinical trial of recombinant human tumor necrosis factor in children with refractory solid tumors: a Pediatric Oncology Group study.

Journal of Clinical Oncology ◽

10.1200/jco.1993.11.11.2205 ◽

1993 ◽

Vol 11 (11) ◽

pp. 2205-2210 ◽

Cited By ~ 35

Author(s):

W L Furman ◽

D Strother ◽

K McClain ◽

B Bell ◽

B Leventhal ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Phase I ◽

Solid Tumors ◽

Tumor Necrosis ◽

Human Tumor ◽

Rest Period ◽

Supplemental Oxygen ◽

Maximum Tolerated Dose ◽

Human Tumor Necrosis Factor ◽

Necrosis Factor

PURPOSE A phase I study was undertaken to determine the toxicity and maximum-tolerated dose (MTD) of recombinant human tumor necrosis factor (rTNF) in children. PATIENTS AND METHODS Twenty-seven patients with recurrent or refractory solid tumors were enrolled on the study. rTNF was administered daily for 5 days by 30-minute intravenous (IV) infusion, and doses were escalated in cohorts of three to six patients. Courses were repeated after a 9-day rest period, if toxicity was tolerable. Daily doses ranged from 100 to 350 micrograms/m2. RESULTS Most courses were associated with grade I/II fever, rigors, nausea, or vomiting. Three patients experienced moderate dyspnea that responded to supplemental oxygen. All abnormalities resolved on discontinuation of the infusion. One patient had a cardiac arrest 90 minutes after receiving the first dose of rTNF and died 10 days later of related complications. In two other patients, rTNF was discontinued due to persistent grade IV hypotension. Toxicities were not consistently related to dose and no cumulative effects were noted. The dose-limiting toxicity was transient hepatic dysfunction, which occurred in three of six patients receiving 350 micrograms/m2; this toxicity was rapidly reversed on discontinuation of the rTNF. One patient, whose non-Hodgkin's lymphoma had recurred after bone marrow transplantation, had a partial response. Disease was stabilized in two patients. CONCLUSION We recommend that phase II testing proceed at a dose of 300 micrograms/m2/d on the schedule described.

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