PHASE-I TRIAL OF CYCLOPHOSPHAMIDE, DOXORUBICIN, AND 5-FLUOROURACIL PLUS INTERFERON-ALPHA-2B IN PATIENTS WITH ADVANCED BREAST-CANCER

Alpha-interferon (IFN-alpha) enhances the activity of 5-fluorouracil i n patients with advanced colorectal carcinoma. Preclinical evidence su ggests a similar potential role for IFN-alpha combined with cyclophosp hamide, doxorubicin (Adriamycin, Adria laboratories, Columbus, OH), an d 5-fluorouracil (CAF) in advanced adenocarcinoma of the Breast. To de termine a maximum tolerated dose of IFN-alpha that could be combined w ith CAF and that did not compromise CAF dose intensity and to determin e the effect of IFN-alpha on the pharmacokinetics of doxorubicin, a ph ase I study of IFN-alpha plus CAF was performed by the Eastern Coopera tive Oncology Group. Nine patients with advanced breast cancer receive d CAF (cyclophosphamide at 100 mg/m2/day p.o. on days 1-14, doxorubici n at 30 mg/m2 and 5-fluorouracil at 500 mg/m2 i.v. bolus on days 1 and 8) plus IFN-alpha (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. Es calation of the IFN-alpha dose occurred in cohorts of 3-6 patients if a dose-limiting toxic event (neutropenic fever, platelet nadir of < 25 ,000/mul, > 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-alpha was omitted on day 1, and multiple plasma samples were drawn on day 1 (without IFN-alpha) and day 8 (with IFN-al pha) after each doxorubicin injection and were analyzed for plasma dox orubicin concentration. The maximum tolerated dose of IFN-alpha by our criteria was 1 milliunit/m2, and neutropenia was the predominant toxi c effect that precluded IFN-alpha dose escalation. The dose intensity of CAF achieved with IFN-alpha was identical to that for CAF alone obs erved in prior studies. IFN-alpha had no significant effect on the pha rmacokinetics of doxorubicin, although 3 of 7 patients studied had red uced doxorubicin clearance, ranging from 32% to 69%. Alternative CAF d rug delivery schedules (all drugs given i.v. every 3-4 weeks) that are more amenable to hematopoietic growth factor support may be more suit able to combine with higher doses of IFN-alpha that may produce modula tion.