Multicentre, phase I study with a standard ‘3 + 3’ design in five dose increments. Eligible patients: aged 6 months to 21 years, diagnosis of a solid malignancy failed at least 2 previous lines of therapy. TMZ was administered orally, starting at 100 mg/m2/d, and TPT intravenously over 30 min, starting at 0.75 mg/m2/d over 5 consecutive days every 28 d. 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 8.5 years (range, 3–19 years). Dose-limiting toxicity (grade 4 neutropenia and/or thrombocytopenia lasting more than 7 d) during the first cycle occurred in 2 of 3 patients at level 3 (TMZ 150 mg/m2/d and TPT 1.0 mg/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 150 mg/m2/d and TPT 0.75 mg/m2/d with dose-limiting haematological toxicity. The observed activity deserves further evaluation in paediatric malignancies.