Phase I Study of Interleukin-2 Combined with Interferon-α and 5-Fluorouracil in Patients with Metastatic Renal Cell Cancer

Interferon-α (IFN-α) and interleukin-2 (IL-2) each has produced a 15%-20% response in metastatic renal cell cancer. Combining IFN-α with either IL-2 or 5-fluorouracil (5-FU) enhanced IFN-α activity. We have therefore conducted a Phase I Study combining IL-2, IFN-α, and 5-FU. The patients were continuously infused with IL-2 (1-3x10⁶ u/m²) and 5-FU (600-750 mg/m²) for a 5-day period every 28 days, and IFN-α (4-5x10⁶ u/m²) was injected subcutaneously daily. Lymphokine-activated killer (LAK) and natural killer (NK) cell activity was measured on days 0 and 8.

Twenty-one patients received 76 courses. All primary tumors were controlled by surgery (81%) or angioinfarction. Hematologic toxicity was mild; median nadir of platelets was 117 K/μL and of granulocytes was 1.2 K/μL. Dose-limiting toxicity included mucositis, liver damage, and hypotension. No treatment-related death occurred, and only one patient required intensive-care-unit support. Two patients had an objective response, one of which was a complete response. Increased LAK cell and NK cell activity occurred at all IL-2 dose levels.

Simultaneous delivery of IL-2, IFN-α, and 5-FU is safe and shows antitumor and biologic activity. 5-FU did not appear to suppress IL-2-induced LAK and NK cell activation. Maximum tolerated dose of the three-drug combination is IL-2, 2 × 10⁶ u/m², 5-FU 600 mg/m², and IFN-α, 4 x 1O⁶ u/m².