We conducted a Phase I trial of interferon-alpha-2a (IFN-alpha-2a) plus combination chemotherapy consisting of cyclophosphamide, vincristine, prednisone, and doxorubicin (COPA) in order to determine the maximum dose of IFN-alpha-2a that could be administered without compromising the dose intensity of COPA. Twenty-one patients received IFN-alpha-2a intramuscularly on days 1-5, followed by 600 mg/m2 cyclophosphamide intravenously (i.v.) on day 8; 50 mg/m2 doxorubicin i.v. on day 8; 1.2 mg/m2 vincristine i.v. on day 8; and 100 mg/m2 prednisone orally on days 8-12. IFN doses were escalated between patient groups; 7 patients received 12 x 10(6) U/m2, 11 patients received 6 X 10(6) U/M2, and 3 patients received 12 X 10(6)/m2. Because 79% of the cycles of COPA administered at the third dose level required a delay for hematologic recovery, further patient accrual at this dose level ceased. Grade III or IV granulocytopenia occurred on day 1 in 6, 9, and 0 of the patients treated at the three dose levels. Granulocyte counts rapidly recovered, however, and did not result in a delay in chemotherapy administration on day 8 in 94% of the cycles at the first two dose levels. The mean hematocrit following five cycles of therapy dropped from 40 to 31%. Only two patients required dose reductions due to constitutional symptoms related to the IFN-alpha-2a. Eight responses were observed, including five of five patients with nonHodgkin's lymphomas, one of five with melanoma, one of six with renal cell carcinoma, and one of one with adenoid cystic carcinoma. One patient with metastatic melanoma remains in a complete response on maintenance IFN-alpha-2a for three years. We conclude that 6 X 10(6) U/m2 of IFN-alpha-2a can be administered to cancer patients without significantly compromising the dose intensity of COPA. This observation, and the demonstrated activity of IFN-alpha-2a plus COPA (I-COPA) in low and intermediate grade histology nonHodgkin's lymphomas, provides the basis for the randomized Phase III trial comparing COPA to I-COPA in these neoplasms, which is currently being conducted in the Eastern Cooperative Oncology Group.