title: Phase I study of a combination of recombinant tumor necrosis factor-alpha and recombinant interferon-gamma in cancer patients.
abstract: Combinations of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) demonstrate synergistic antiproliferative activity in vitro. Therefore, we initiated a clinical study of recombinant TNF-alpha (rTNF-alpha) and rIFN-gamma combination therapy in humans. Twenty-five patients with metastatic cancer received both rTNF-alpha and rIFN-gamma by intramuscular injection for 5 consecutive days every 2 weeks for a total of 4 weeks. The dose levels were 5/5, 10/5, 10/10, 25/10, 25/25, 50/25, 50/50, 75/50, and 75/75 micrograms/m2 per day of rTNF-alpha/rIFN-gamma. A minimum of 2 patients were entered sequentially at each dose level. If the first 2-week cycle of therapy was well tolerated, the dose was increased to the next highest dose level during the second 2-week cycle. Fever, chills, and fatigue were observed at all doses. Severity of symptoms corresponded to increasing dose levels. Although TNF is identical to a molecule known as "cachectin," the vast majority of our patients did not lose weight while on study. However, alterations in lipid metabolism occurred and were manifested by a median change in triglyceride values of +40 mg/dl (range, -130 to +318 mg/dl), and in cholesterol values of -30 mg/dl (range, -103 to +2 mg/dl). The maximum tolerated dose was 75 micrograms/m2 of rTNF-alpha combined with 50 micrograms/m2 of rIFN-gamma, with dose-limiting side effects being mainly constitutional symptoms. A dose-related suppression in granulocyte and platelet counts was observed. Hematologic parameters returned to baseline within 72 h after therapy was discontinued, and neither infection nor bleeding occurred. Ten of 22 evaluable patients had stable disease for a median of 8 weeks (range, 4-21 weeks); 12 patients showed progressive disease. This study will form the framework for phase II trials of rTNF-alpha and rIFN-gamma combination therapy.
authors.affiliation: Department of Clinical Immunology, University of Texas, M.D. Anderson Cancer Center, Houston 77030.
authors.forename: R
authors.initials: R
authors.lastname: Kurzrock
authors.forename: B
authors.initials: B
authors.lastname: Feinberg
authors.forename: M
authors.initials: M
authors.lastname: Talpaz
authors.forename: S
authors.initials: S
authors.lastname: Saks
authors.forename: J U
authors.initials: JU
authors.lastname: Gutterman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000917:Antibody Formation; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology
chemical_list: D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma