Preliminary clinical trials using intravenous interleukin-2 (IL-2) at moderate or high doses concurrently with interferon-alpha (IFN) suggested that the combination could produce superior response rates in comparison to the single agents. In order to reduce acute toxicity and to test whether extending the duration of treatment would increase efficacy, we conducted a phase I study to determine the doses of IL-2/IFN that could be administered subcutaneously on an outpatient basis for prolonged periods. A secondary objective was to characterize the immunologic effects of the regimen. IL-2 was administered daily x 5 each week in all cohorts. The first cohort (IL-2 dose 3 million Roche units/m2/d) received IFN (2.5 mu/m2) TIW; only 3/6 completed at least 1 month at full doses due to chronic, disabling constitutional symptoms (fatigue, fever, nausea, and vomiting). Subsequently, all cohorts received IFN daily (in an attempt to induce tachyphylaxis to systemic symptoms), and dose escalation began at 1.5 mu/m2 of both agents. Attempts to escalate the interferon (to 3 mu/m2, 6 patients) or IL-2 (to 3 mu/m2, 4 patients) in subsequent cohorts again produced toxicity incompatible with chronic outpatient administration. A total of 16 patients were entered at the MTD (1.5 mu/m2 of both agents); 11/15 who were evaluable for toxicity tolerated outpatient treatment at full doses for at least 1 month, and 6 received from 4-9 months of treatment without dose reductions. In order to determine the role of IFN in the IL-2/IFN regimen with regard to toxicity and immune modulation, 21 patients received IL-2 alone in the first month at 1.5 mu/m2/d or 3 mu/m2/d before receiving the combination at the established MTD. Overall, 7 partial responses were seen, all in RCC patients. This regimen has substantial activity in RCC and can be administered with minimal to moderate toxicity in an outpatient setting.
