TRIAL OF ICRF-187 TO DECREASE DOXORUBICIN CARDIOMYOPATHY

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Doxorubicin induced cardiomyopathy limits the cumulative dose of this drug which can be administered to cancer patients. We propose a randomized clinical trial to test the effectiveness of the agent ICRF-187 in preventig this cardiomyopathy in 132 patients with advanced inoperable breat cancer who will be receiving a doxorubicin based combination of cytotoxic drugs. ICRF-187 was chosen because in extensive animal studies it consistently prevented the pathologic changes of chronic doxorubicin cardiomyopathy. The drug has also been tested in humans in clinical trials and has been shown to be non-toxic in the doses proposed for this study. All patients will receive 5- fluorouracil, doxorubicin, and cyclophosphamide and will be randomized to receive ICRF-187. The ICRF will be given as an I.V. bolus 30 minutes prior to the administrations of doxorubicin. Patients will be monitored for acute toxicity to the chemotherapeutic agents by clinical examination, blood examinations and x-rays. The primary endpoint of the study is the development of cardiotoxicity which will be assessed by clinical examination, falls in left ventricular ejection fractions as measured by resting and exercise nucler gated pool scans and pathologic changes seen in right ventricular endomyocardial biopsies. Biopsies will be done in 36 patients. The study was started and accrued 87 patients preliminary results indicated statistically significant cardiac protection as measured by nuclear gated pool scans. Clinical and biopsy data all suggest cardiac protection but are not statistically significant at this time. Non cardiac toxicity and antitumor efficacy of the drug combination are not elected by the addition of ICRF-187 in this dose and schedule. This proposal is to complete the original accrual of injection and complete data analysis.