To evaluate maximum tolerated dose and recommended dose (RD) for phase II studies of topotecan (TPT) combined with temozolomide (TMZ) (TOTEM) in children and adolescents with relapsed or refractory solid malignancies.

Multicentre, phase I study with a standard ‘3+3’ design in five dose increments. Eligible patients: aged 6months to 21years, diagnosis of a solid malignancy failed at least 2 previous lines of therapy. TMZ was administered orally, starting at 100mg/m²/d, and TPT intravenously over 30min, starting at 0.75mg/m²/d over 5 consecutive days every 28d. A pharmacokinetics analysis was performed on Day 1 and Day 5 of cycle 1.

Between February and October 2007, 16 patients were treated. The median age was 8.5years (range, 3–19years). Dose-limiting toxicity (grade 4 neutropenia and/or thrombocytopenia lasting more than 7d) during the first cycle occurred in 2 of 3 patients at level 3 (TMZ 150mg/m²/d and TPT 1.0mg/m²/d) and was always manageable. Confirmed complete and partial responses were observed in 4 patients (25%), three with metastatic neuroblastoma and one with high-grade glioma. Seven patients had a stable disease. Pharmacokinetic data show a wide inter-individual variability. No significant differences were observed between plasma TMZ and TPT concentrations on Day 1 and Day 5 indicating the absence of pharmacokinetic interaction between the drugs.

The RD for the combination is TMZ 150mg/m²/d and TPT 0.75mg/m²/d with dose-limiting haematological toxicity. The observed activity deserves further evaluation in paediatric malignancies.