Phase I study of topotecan in combination with temozolomide (TOTEM) in relapsed or refractory paediatric solid tumours

• Published in: European journal of cancer (1990) 2010-10, Vol.46 (15), p.2763-2770
• Main Authors: Rubie, Hervé, Geoerger, Birgit, Frappaz, Didier, Schmitt, Antonin, Leblond, Pierre, Ndiaye, Anna, Aerts, Isabelle, Deley, Marie-Cécile Le, Gentet, Jean-Claude, Paci, Angelo, Chastagner, Pascal, Dias, Nathalie, Djafari, Latifa, Pasquet, Marlène, Chatelut, Etienne, Landman-Parker, Judith, Corradini, Nadège, Vassal, Gilles
• Format: Article
• Language: English
• Subjects: Adolescent; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Child; Child, Preschool; Dacarbazine - administration & dosage; Dacarbazine - adverse effects; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacokinetics; Hematology, Oncology and Palliative Medicine; Humans; Infant; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Recurrence, Local - drug therapy; Neoplasms - drug therapy; Paediatrics; Pharmacology. Drug treatments; Phase I; Temozolomide; Topotecan; Topotecan - administration & dosage; Topotecan - adverse effects; Topotecan - pharmacokinetics; Treatment Outcome; Tumor Protein, Translationally-Controlled 1; Tumors; Young Adult
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2010.05.004

Abstract Purpose 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. Patients and methods 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. Results 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. Conclusions 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.