Doxorubicin is a chemotherapeutic drug active against a variety of malignancies. The most important dose-limiting side effect of chronic doxorubicin treatment is cardiomyopathy. Certain compounds can modify doxorubicin cardiac toxicity in animals. In early studies, ICRF-159 caused a significant reduction of daunorubicin toxicity. ICRF-187 is the water soluble isomer of ICRF-159 and reduces the cardiac toxicity of daunorubicin and doxorubicin in rabbits, hamsters and dogs. The encouraging results in animals led to a preliminary study of human subjects in our laboratory. The group receiving bolus intravenous ICRF-187 30 minutes prior to doxorubicin appears to be having less change of cardiac non-invasive function tests than the group receiving placebo. The purpose of the present study is to further evaluate ICRF-187's ability to ameliorate doxorubicin induced cardiac toxicity. Patients will be randomized to pretreatment with either ICRF-187 or placebo in a double-blinded fashion. Baseline evaluation will include a history and physical examination, chest x-ray, electrocardiogram, systolic time intervals, echocardiograms, nuclear angiogram, complete blood count, liver enzymes, tumor status and performance status. Blood tests, the echocardiogram and systolic time intervals will be repeated immediately prior to subsequent doses of doxorubicin. A total evaluation including all the tests performed at baseline will be repeated when the cumulative doxorubicin dose is 300 and 500 mg/m2. In addition, an endomyocardial biopsy will be performed at baseline and at cumulative doses of 300 and 500 mg/m2 in those subjects who consent. The two groups of patients will be evaluated for tumor response and side effects to the two drug regimens. Cardiac function studies will be compared between the two groups (45 in each group) by the two way analysis of variance. The endomyocardial biopsy will receive a grade (Billingham criteria) and the groups will also be compared by analysis of variance. The successful completion of this study should demonstrate whether ICRF-187 effectively prevents doxorubicin-induced cardiac functional and histologic changes.
