TY - JOUR
T1 - Phase i study of topotecan in combination with temozolomide (TOTEM) in relapsed or refractory paediatric solid tumours
AU - Rubie, Hervé
AU - Geoerger, Birgit
AU - Frappaz, Didier
AU - Schmitt, Antonin
AU - Leblond, Pierre
AU - Ndiaye, Anna
AU - Aerts, Isabelle
AU - Deley, Marie Cécile Le
AU - Gentet, Jean Claude
AU - Paci, Angelo
AU - Chastagner, Pascal
AU - Dias, Nathalie
AU - Djafari, Latifa
AU - Pasquet, Marlne
AU - Chatelut, Etienne
AU - Landman-Parker, Judith
AU - Corradini, Nadge
AU - Vassal, Gilles
N1 - Funding Information:
We thank all patients and their parents who participated in the trial and the teams of the treating centres. This work was supported by a Grant from the Clinical Research Program from the French Ministry of Health (PHRC 2006), the Ligue Nationale Contre le Cancer within the framework of the project entitled Ealy Therapeutics in Pediatric Oncology, Enfants et Santé, the Société Française des Cancers de l’Enfant, Association Hubert Gouin, Schering-Plough France and Glaxo-Smith Kline France for their financial support.
PY - 2010/10/1
Y1 - 2010/10/1
N2 - 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/m 2/d and TPT 0.75 mg/m2/d with dose-limiting haematological toxicity. The observed activity deserves further evaluation in paediatric malignancies.
AB - 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/m 2/d and TPT 0.75 mg/m2/d with dose-limiting haematological toxicity. The observed activity deserves further evaluation in paediatric malignancies.
KW - Paediatrics
KW - Phase I
KW - Temozolomide
KW - Topotecan
UR - http://www.scopus.com/inward/record.url?scp=77957203514&partnerID=8YFLogxK
U2 - 10.1016/j.ejca.2010.05.004
DO - 10.1016/j.ejca.2010.05.004
M3 - Article
C2 - 20558056
AN - SCOPUS:77957203514
SN - 0959-8049
VL - 46
SP - 2763
EP - 2770
JO - European Journal of Cancer
JF - European Journal of Cancer
IS - 15
ER -