Phase I evaluation of recombinant tumor necrosis factor given in combination with recombinant interferon-gamma

In light of in vitro and preclinical animal model data suggesting potential additive or synergistic antitumor effects from the combined use of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), we conducted a phase I study employing escalating doses of each agent in 36 patients with solid tumors to determine the maximum tolerated dose (MTD). Patients: were given an intramuscular (i.m.) injection of IFN-γ, followed 5 min later by an i.m. injection of TNF-α, each agent in different sites, every other day for ten doses over 20 days. Patients: received 10, 50, or 100 μ/m² of each agent throughout the treatment course. No dose modifications were made. Patients: suffering serious toxicity had therapy stopped and were considered to be offstudy. All patients experienced fatigue, and 36% spent over half their time in bed on treatment days. Fever and chills were nearly universal. Mild to moderate elevations in serum transaminase levels were noted in 44% of patients, and 44% developed transient microscopic hematuria. Although 81% of patients had anorexia, only 17% of patients lost more than 3 kg of body wt during the 3 weeks of therapy. Because two of three patients receiving 100 μ g/m² of both agents developed serious toxicity (one fever <105°F, one thrombocytopenia 43,000/mm³), the MTD was established to be 100 μ g/m² of IFN-γ plus 50 μgm² of TNF-α. The use of aspirin did not significantly alter the toxic effects of the agents. One patient with melanoma had a mixed response and one patient with mesothelioma transiently cleared his ascites of malignant cells.