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


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/m(2)/d, and TPT intravenously over 30 min, starting at 0.75 mg/m(2)/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/m(2)/d and TPT 1.0 mg/m(2)/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/m(2)/d with dose-limiting haematological toxicity. The observed activity deserves further evaluation in paediatric malignancies.
Rubie
Hervé
H
Hôpital des Enfants, Toulouse, France. rubie.h@chu-toulouse.fr
Geoerger
Birgit
B
Frappaz
Didier
D
Schmitt
Antonin
A
Leblond
Pierre
P
Ndiaye
Anna
A
Aerts
Isabelle
I
Le Deley
Marie-Cécile
MC
Gentet
Jean-Claude
JC
Paci
Angelo
A
Chastagner
Pascal
P
Dias
Nathalie
N
Djafari
Latifa
L
Pasquet
Marlène
M
Chatelut
Etienne
E
Landman-Parker
Judith
J
Corradini
Nadège
N
Vassal
Gilles
G
D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006801:Humans; D007223:Infant; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009369:Neoplasms / Q000188:drug therapy*; D000077204:Temozolomide; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D000090324:Tumor Protein, Translationally-Controlled 1; D055815:Young Adult
D000090324:Tumor Protein, Translationally-Controlled 1; D003606:Dacarbazine; D019772:Topotecan; D000077204:Temozolomide