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 of continuous infusion of high-dose VP-16 in combination with high-dose melphalan (HDM) for conditioning before autologous bone marrow transplantation (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 conventional chemotherapy with a mean number of six drugs. Surgery of the primary tumor had been performed in 12/13. We performed a dose-escalating study of VP-16 from 1800 mg/m²/72 h with 300 mg/m²/72 h dose increments according to toxicity. VP-16 was administered as a 72-h i.v. infusion. Melphalan (140 mg/m²/day) was administered once as an i.v. push. VP-16 pharmacokinetics were analyzed in 12 patients. Five children received 1800 mg/m²/72 h of VP-16, five received 2100 mg/m²/72 h and three, 2400 mg/m²/72 h. The mean duration of granulocytopenia (< 0.5 x 10⁹/l) was 24 days and thrombocytopenia (< 50 x 10⁹/l) was 36 days. No major infectious complications occurred. Gastrointestinal (GI) toxicity was the dose-limiting toxicity. Five severe manifestations of GI toxicity in three patients led us to consider 2400 mg/m²/72 h as the MTD. The mean VP-16 clearance rate was 17.3 ml/min/m² with continuous infusion. A mean steady-state plasma concentration of 24.2 μg/ml (s.d. = 2) and 28.3 μg/ml (s.d. = 1.9) was achieved at the 1800 mg/ml and 2100 mg/m² dose levels, respectively. GI toxicity is dose limiting when VP-16 at 2400 mg/m²/72 h, is associated with HDM. When given as a continuous i.v. infusion, at 2100 mg/m²/72 h, VP-16 associated with HDM is well tolerated before ABMT in young heavily pre-treated children.