The combination of interleukin-2 (IL-2) and interferon-alfa demonstrated synergistic antitumor activity in preclinical animal tumor models, even at doses substantially below their individual maximum tolerated dose (MTD). Based on these data, we initiated a phase 1 trial of IL-2 and interferon- alfa to determine an optimal regimen for chronic outpatient treatment. Both agents were administered subcutaneously. All patients received IL-2 daily for 5 days each week. The first dose level was 3 mu/m2/d of IL-2, and 2.5 mu/m2 of interferon-alfa thrice weekly. Due to excessive toxicity which required dose reductions early in treatment in 2 of the 5 evaluable patients, the starting dose of IL-2 and interferon-alfa was decreased to 1.5 mu/m2/d, and the interferon-alfa was given daily (rather than TIW) to allow for tachyphylaxis to its systemic toxicities. Although dose- escalation of first IL-2 and then interferon-alfa was attempted, the doses which were tolerated during chronic outpatient therapy were 1.5 mu/m2/d of each agent. A total of 32 patients were accrued to the study, 15 at the MTD. Toxicities included fever, chills, diarrhea, nausea, vomiting, weight loss, hypotension requiring hydration or pressors, and elevations of serum creatinine, bilirubin, and transaminases. One patient developed a neurologic syndrome resembling a focal stroke which resolved. Three partial responses were seen in this study, all in patients with renal cell carcinoma (19 renal cell carcinoma patients entered). We conclude that 1.5 mu/m2 of IL-2 given SQ daily can be given on an outpatient basis to a majority of patients and has activity in patients with renal cell carcinoma.
