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Phase I Trial of Cyclophosphamide, Doxorubicin, and 5-Fluorouracil plus Interferon-2b in Patients with Advanced Breast Cancer¹

Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, New York 10467 [J. A. S., S. W., E. L. S., J. P. D.], Kaplan Cancer Center, New York University, New York, New York 10016 [L. L.], and Fairfax Hospital, Annandale, Virginia 22003 [N. J. R.], for the Eastern Cooperative Oncology Group, Denver, Colorado 80214

-Interferon (IFN-) enhances the activity of 5-fluorouracil in patients with advanced colorectal carcinoma. Preclinical evidence suggests a similar potential role for IFN- combined with cyclophosphamide, doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH), and 5-fluorouracil (CAF) in advanced adenocarcinoma of the breast. To determine a maximum tolerated dose of IFN- that could be combined with CAF and that did not compromise CAF dose intensity and to determine the effect of IFN- on the pharmacokinetics of doxorubicin, a phase I study of IFN- plus CAF was performed by the Eastern Cooperative Oncology Group. Nine patients with advanced breast cancer received CAF (cyclophosphamide at 100 mg/m²/day p.o. on days 1–14, doxorubicin at 30 mg/m² and 5-fluorouracil at 500 mg/m² i.v. bolus on days 1 and 8) plus IFN- (1 milliunit/m², n = 6, or 2 milliunits/m², n = 3) given s.c. on days 1, 3, 5, and 8 (1 h prior to the doxorubicin and 5-FU injection on days 1 and 8) of each cycle every 28 or more days. Escalation of the IFN- dose occurred in cohorts of 3–6 patients if a dose-limiting toxic event (neutropenic fever, platelet nadir of < 25,000/µl, > 2-week treatment delay, or a >50% dose reduction in day 8 CAF) occurred during the first two cycles in 0 of 3 or 1 of 6 patients. During cycle 1, IFN- was omitted on day 1, and multiple plasma samples were drawn on day 1 (without IFN-) and day 8 (with IFN-) after each doxorubicin injection and were analyzed for plasma doxorubicin concentration. The maximum tolerated dose of IFN- by our criteria was 1 milliunit/m², and neutropenia was the predominant toxic effect that precluded IFN- dose escalation. The dose intensity of CAF achieved with IFN- was identical to that for CAF alone observed in prior studies. IFN- had no significant effect on the pharmacokinetics of doxorubicin, although 3 of 7 patients studied had reduced doxorubicin clearance, ranging from 32% to 69%. Alternative CAF drug delivery schedules (all drugs given i.v. every 3–4 weeks) that are more amenable to hematopoietic growth factor support may be more suitable to combine with higher doses of IFN- that may produce modulation.

¹ Supported in part by the National Cancer Institute, Department of Health and Human Services Grants P30CA13330 and 5U10CA14958, and by American Cancer Society Career Development Award 92-274 (J. A. S.).

² To whom requests for reprints should be addressed, at Albert Einstein Cancer Center, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467.

Received 4/15/93. Accepted 5/24/93.