PHASE-I STUDY OF HIGH-DOSE CONTINUOUS INTRAVENOUS-INFUSION OF VP-16 IN COMBINATION WITH HIGH-DOSE MELPHALAN FOLLOWED BY AUTOLOGOUS BONE-MARROW TRANSPLANTATION IN CHILDREN WITH STAGE-IV NEUROBLASTOMA

The purpose of the study was to determine the maximum tolerated dose o f continuous infusion of high-dose VP-16 in combination with high-dose melphalan (HDM) for conditioning before autologous bone marrow transp lantation (ABMT), Thirteen children (median age 27 months) with stage IV neuroblastoma were treated with high-dose VP-16 and HDM followed by ABMT as consolidation treatment, All had previously received conventi onal chemotherapy with a mean number of six drugs, Surgery of the prim ary tumor had been performed in 12/13, We performed a dose-escalating study of VP-16 from 1800 mg/m(2)/72 h with 300 mg/m(2)/72 h dose incre ments according to toxicity, VP-16 was administered as a 72-h i.v. inf usion, Melphalan (140 mg/m(2)/day) was administered once as an i.v. pu sh, VP-16 pharmacokinetics were analyzed in 12 patients, Five children received 1800 mg/m(2)/72 h of VP-16, five received 2100 mg/m(2)/72 h and three, 2400 mg/m(2)/72 h, The mean duration of granulocytopenia (< 0.5 x 10(9)/l) was 24 days and thrombocytopenia (<50 x 10(9)/l) was 36 days, No major infectious complications occurred, Gastrointestinal (G I) toxicity was the dose-limiting toxicity, Five severe manifestations of GI toxicity in three patients led us to consider 2400 mg/m(2)/72 h as the MTD, The mean VP-16 clearance rate was 17.3 ml/min/m(2) with c ontinuous infusion, A mean steady-state plasma concentration of 24.2 m u g/ml (s.d. = 2) and 28.3 mu g/ml (s.d. = 1.9) was achieved at the 18 00 mg/ml and 2100 mg/m(2) dose levels, respectively, GI toxicity is do se limiting when VP-16 at 2400 mg/m(2)/72 h, is associated with HDM, W hen given as a continuous i.v. infusion, at 2100 mg/m(2)/72 h, VP-16 a ssociated with HDM is well tolerated before ABMT in young heavily pre- treated children.