AMONAFIDE - AN ACTIVE AGENT IN THE TREATMENT OF PREVIOUSLY UNTREATED ADVANCED BREAST-CANCER - A CANCER AND LEUKEMIA GROUP-B STUDY (CALGB-8642)

Amonafide is a new imide derivative of naphthalic acid, The drug had d emonstrated significant activity in preclinical studies and some activ ity in Phase I trials, The drug is extensively metabolized and detecte d in plasma and urine, Its toxicity has previously been correlated to the formation of an active metabolite, N-acetyl-amonafide. Amonafide w as chosen for inclusion in the Cancer and Leukemia Group B (CGLGB) mas ter metastatic breast cancer protocol, CALGB 8642 randomizes previousl y untreated metastatic breast cancer patients either to one of several Phase LI agents given for up to four cycles and then followed by stan dard cyclophosphamide-doxorubicin-5-fluorouracil or to immediate treat ment with standard cyclophosphamidedoxorubicin-5-fluorouracil. The end point of CALGB 8642 is to assess the difference in survival, toxicity , and overall response when limited exposure to Phase II agents preced es standard chemotherapy. This report deals only with amonafide as a P hase II agent. Comparisons with the cyclophosphamide-doxorubicin-5-flu orouracil arm will not be addressed, Patients had to have histological ly documented measurable breast cancer and a performance status of 0-1 . Patients could not have had prior chemotherapy for metastatic diseas e, Prior adjuvant chemotherapy was permitted. Patients could not have visceral crisis, Amonafide was given at 300 mg/m(2)/day i.v. for 5 day s, and repeated at 21-day intervals for a maximum of four cycles, Esca lation and reduction in dose was mandated dependent on hematotoxicity or lack thereof, Toxicity was primarily hematological and bimodal: 32% had grade 3 or 4 leukopenia and 24% had grade 3 or 4 thrombocytopenia ; 22% had no leukopenia and 44% had no thrombocytopenia, The response rate was 18%, including one complete response. When response was analy zed by hematological toxicity, there was a 35.7% response if patients had leukopenia grade 3/4 (versus 8.3%, P = 0.08). There was a 50% resp onse if patients had thrombocytopenia grade 3/4 (versus 7.1%, P = <0.0 1). We conclude that amonafide is somewhat active in previously untrea ted breast cancer patients. There may be a steep dose-response curve, based on the significant correlation between myelosuppression and resp onse, Rates of responses in patients adequately dosed (i.e., with sign ificant hematotoxicity) dth amonafide ranged from 35 to 50%. Further s tudies will incorporate individualized dosing based on pretreatment ac etylator phenotyping.