Target-driven exploratory study of imatinib mesylate in children with solid malignancies by the Innovative Therapies for Children with Cancer (ITCC) European Consortium.
OBJECTIVE
To explore imatinib efficacy and pharmacokinetics in children and adolescents with refractory/relapsing solid tumours, expressing imatinib-sensitive receptor tyrosine kinases.


METHODS
Exploratory study on imatinib in tumours expressing, at least, one of the receptors KIT or platelet-derived growth factor receptor (PDGFR). Standard radiological response evaluation, pharmacokinetics, gene mutations and positron emission tomography imaging were assessed.


RESULTS
Thirty-six patients (median age: 13.7 years) with brain (12), mesenchymal/bone (14) or other solid tumours, received imatinib 340 mg/m(2)/d over a total of 255 months. Fifteen tumours expressed KIT in 30% cells, 19 expressed PDGFRA and 25 expressed PDGFRB. Twenty patients experienced grades 1-2 treatment-related toxicities. Ten patients achieved stable disease; one chordoma had metabolic response. Pharmacokinetic data showed high inter-patient variability (variation coefficient: 44% and 53% for plasma imatinib and CGP 74588 AUCs, respectively).


CONCLUSIONS
Imatinib was tolerated well, but failed to show efficacy according to standard criteria in paediatric malignancies expressing KIT or PDGFR.
Department of Paediatrics, Institut Gustave Roussy, 39 Rue Camille Desmoulins, 94805 Villejuif, France. geoerger@igr.fr
Birgit
B
Geoerger
Bruce
B
Morland
Anna
A
Ndiaye
Francois
F
Doz
Gabriel
G
Kalifa
Anne
A
Geoffray
Fabienne
F
Pichon
Didier
D
Frappaz
Etienne
E
Chatelut
Paule
P
Opolon
Sharon
S
Hain
Francoise
F
Boderet
Jacques
J
Bosq
Jean-Francois
JF
Emile
Marie-Cecile
MC
Le Deley
Renaud
R
Capdeville
Gilles
G
Vassal
D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001549:Benzamides; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005091:Exons / Q000187:drug effects / Q000235:genetics; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome; D055815:Young Adult
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020797:Receptor, Platelet-Derived Growth Factor beta