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 clinical phase I trial of doxorubicin coupled to dextran (70000 m.w.). The drug was administered as single dose i.v. every 21-28 days. Thirteen patients have received a total of 24 courses (median 2; range 1 - 3). At the starting dose of 40 Mg/M2 doxorubicin equivalent (DOXeq), WHO grade IV thrombocytopenia was noted in 2/2 patients. WHO grade IV hepatotoxicity and WHO grade III cardiotoxicity were noted in a patient with preexisting heart disease. Five patients were treated with 12.5 mg/m2 DOXeq. Maximal toxicity at this dose level was WHO grade III thrombocytopenia and local phlebitis (WHO grade II) in 115 patients, elevation of alkaline phosphatase (WHO grade III) and WHO grade III vomiting in another patient. Subsequently, five patients received 20 Mg/M2 DOXeq. Hepatotoxicity was noted in 515 patients (I x WHO grade IV, 1 x WHO grade III). Thrombocytopenia was noted in 3/5 patients (I x WHO grade IV, 2 x WHO grade III). At 12.5 Mg/M2 DOXeq, a patient diagnosed with a malignant fibrous histiocytoma had stable disease for 4 months. Pharmacokinetic analyses of total and free doxorubicin were performed in plasma and urine. The maximum peak plasma concentration (ppc) for total DOX was 12.3 mug/ml at 40 mg/m2 DOXeq. The area under the plasma concentration time curve (AUC) ranged from 28.83-80.21 mug/ml*h with dose-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 maximal 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 DOXeq.