A PHASE-I AND PHARMACOKINETIC STUDY OF TALLIMUSTINE [PNU152241 (FCE-24517)] IN PATIENTS WITH ADVANCED CANCER

Tallimustine [PNU 152241 (FCE 24517)] is a synthetic derivative of the DNA minor groove binder distamycin A, in which the NH2-terminal formy l group is substituted by benzoyl mustard, In this Phase I clinical tr ial, patients with advanced solid tumors received i.v. bolus injection s of tallimustine daily for 3 consecutive days, Patients were treated at six dosage levels of 33.3 mu g/m(2)/day to 250 (mu g/m(2)/day for 3 consecutive days, with courses of therapy repeated every 28 days, Det ailed pharmacokinetic blood sampling was performed during the first 3 days of the first course of tallimustine, The plasma samples were anal ayzed by high-performance liquid chromatography with UV detection, For ty-eight eligible patients were treated at all six dosage levels, The dominant dose-related toxicity of tallimustine was neutropenia, becomi ng dose limiting at 250 mu g/m(2)/day. At this dosage level, one patie nt experienced febrile neutropenia, and a second patient died on study of indeterminate cause, Thrombocytopenia was not observed, and only 1 0 patients developed anemia <8.0 gm/dl, Sporadic elevation of liver en zymes or bilirubin was observed but was not dose related. Pharmacokine tic analysis gave reliable results for 33 patients, For most patients, analysis of the data best fit a three-exponential model, Dose-related increases in areas under the concentration-time curve and end-of-infu sion concentrations were observed, There was no significant plasma acc umulation of tallimustine over the 3 days of administration, The termi nal half-life of tallimustine in individual patients ranged from 6.83 to 39.02 h following the last dose, In summary, the recommended Phase II dosage for tallimustine is 200 mu g/m(2)/day for 3 consecutive days every 28 days, Neutropenia is the principal toxicity of this agent at this dosage and schedule.