PHARMACOKINETICS OF ANTIGANGLIOSIDE GD2 MAB 14G2A IN A PHASE-I TRIAL IN PEDIATRIC CANCER-PATIENTS

A phase I trial of a murine anti-ganglioside (GD2) monoclonal antibody (mAb) 14G2a was conducted in 14 neuroblastoma patients and 1 osteosar coma patient to assess its safety toxicity and pharmacokinetics in ped iatric patients. The pharmacokinetics of mAb 14G2a were biphasic with a t(1 2)(alpha) of 2.8 +/- 2.8 h and a t(1 2)(b)eta of 18.3 +/- 11 8 h . In general. t(1 2)(b)eta was dose-dependent with a level of signific ance of P = 0.036, and it reached a plateau at doses of 250 mg/m(2) or more. Overall the peak serum levels were dose-dependent at P < 0.001. However, they demonstrated an abrupt increase betw een doses of 100 m g m(2) and 250 mg m(2). The latter two suggest a saturable mechanism f or mAb elimination. In addition peak serum concentrations sere observe d earlier at higher mAb doses which indicates the achievement of a ste ady state. The t(1 2)(beta) of mAb 14G2a in children appears to be sho rter than in adults. Furthermore 7 patients demonstrated a considerabl e decrease in t(1 2)(b)eta following retreatment with 14G2a. This was paralleled by high human anti-(mouse Ig) antibody levels. This study r epresents the first comprehensive analysis of murine mAb pharmacokinet ics in children and will be useful in the future design of mAb therapy .