PHASE-I CLINICAL AND PHARMACOKINETIC TRIAL OF DEXTRAN CONJUGATED DOXORUBICIN (AD-70, DOX-OXD)

Coupling of anthracyclines to high-molecular-weight carriers may alter drug disposition and improve antitumor effects. We have performed a c linical phase I trial of doxorubicin coupled to dextran (70000 m.w.). The drug was administered as single dose i.v. every 21-28 days. Thirte en patients have received a total of 24 courses (median 2; range 1 - 3 ). At the starting dose of 40 Mg/M2 doxorubicin equivalent (DOXeq), WH O grade IV thrombocytopenia was noted in 2/2 patients. WHO grade IV he patotoxicity and WHO grade III cardiotoxicity were noted in a patient with preexisting heart disease. Five patients were treated with 12.5 m g/m2 DOXeq. Maximal toxicity at this dose level was WHO grade III thro mbocytopenia and local phlebitis (WHO grade II) in 115 patients, eleva tion of alkaline phosphatase (WHO grade III) and WHO grade III vomitin g in another patient. Subsequently, five patients received 20 Mg/M2 DO Xeq. Hepatotoxicity was noted in 515 patients (I x WHO grade IV, 1 x W HO grade III). Thrombocytopenia was noted in 3/5 patients (I x WHO gra de IV, 2 x WHO grade III). At 12.5 Mg/M2 DOXeq, a patient diagnosed wi th a malignant fibrous histiocytoma had stable disease for 4 months. P harmacokinetic analyses of total and free doxorubicin were performed i n plasma and urine. The maximum peak plasma concentration (ppc) for to tal DOX was 12.3 mug/ml at 40 mg/m2 DOXeq. The area under the plasma c oncentration time curve (AUC) ranged from 28.83-80.21 mug/mlh with do se-dependent elimination half lives (t1/2alpha: 0.02-0.87 h; t1/2beta: 2.69-11.58 h; t1/2gamma: 41.44-136.58 h). We conclude that the maxima l tolerated dose (MTD) of AD-70 using this schedule is 40 mg/m2 DOXeq. The recommended dose for clinical phase II studies is 12.5 Mg/M2 DOXe q.