Phase I Study of a Combination of Recombinant Tumor Necrosis Factor-α and Recombinant Interferon-γ in Cancer Patients

Combinations of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) demonstrate synergistic antiproliferative activity in vitro. Therefore, we initiated a clinical study of recombinant TNF-α (rTNF-α) and rIFN-γ combination therapy in humans. Twenty-five patients with metastatic cancer received both rTNF-α and rIFN-γ 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 μg/m² per day of rTNF-α/ rIFN-γ. 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 μg/m² of rTNF-α combined with 50 μg/m² of rIFN-γ, 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-α and rIFN-γ combination therapy.