Summary: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/m2of 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/m2of both agents developed serious toxicity (one fever <105°F, one thrombocytopenia 43,000/mm3), the MTD was established to be 100 μ g/m2of IFN-γ plus 50 μg /m2of 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.