Interferon alfa-2b-cyclophosphamide combination studies: in vitro and phase I-II clinical results

Since interferon alfa-2b (Intron A) is useful as a single agent, it is important to determine if interferon can be combined with standard chemotherapy to improve both response and survival in patients with cancer. Using clonogenic assays, interferon was tested alone and in combination with cyclophosphamide (Cytoxan) or melphalan (Alkeran) using several dose and exposure schedules to evaluate cytotoxicity. In vitro, continuous-exposure interferon produced optimal cell kill. Maximum enhancement of cytotoxicity occurred with cyclophosphamide or melphalan pretreatment (1 hour) and/or simultaneous interferon treatment. Based upon these data, a phase I-II study was designed to determine the tolerance of cancer patients to a fixed dose of cyclophosphamide (150 mg/m2 p.o. daily X 4 days [days 2 to 5]) combined with increasing doses of interferon. Interferon was administered subcutaneously on treatment cycle days 1 to 5, plus days 8, 10, 12, 15, 17, and 19 of the 21-day regimen. Three patients had partial responses: one breast cancer, one angiosarcoma, and one myeloma (mixed). All patients reported mild flu-like symptoms, fatigue, and anorexia. Leukopenia occurred in all patients; three required treatment interruption to allow recovery. Eight patients had a fall in hemoglobin (mean decrease 1.4 g/dL). The combination of cyclophosphamide and interferon was safe and deserves further trial in cancer treatment. However, using this combination schedule, interferon doses greater than or equal to 5 X 10(6) IU were poorly tolerated and compromised administration of full-dose cyclophosphamide.