Innovative Therapies for Children with Cancer pediatric phase I study of erlotinib in brainstem glioma and relapsing/refractory brain tumors.
This multicenter phase I study aimed to establish the recommended dose (RD) of the epidermal growth factor receptor (EGFR) inhibitor erlotinib, given as monotherapy or with radiotherapy to children with malignant brain tumors. Group 1 included patients with refractory or relapsing brain tumors receiving erlotinib alone, and group 2 included newly diagnosed patients with brainstem gliomas receiving radiotherapy and erlotinib. A conventional 3 + 3 dose escalation and a continual reassessment method, respectively, were utilized in 4 dose levels: 75, 100, 125, and 150 mg/m² per day. Fifty-one children were enrolled (30 and 21, respectively); 50 received treatment. The RD of erlotinib was 125 mg/m² per day as monotherapy or in combination with radiotherapy. Overall, 230 adverse events in 44 patients were possibly treatment related (216, grades 1 and 2; 9, grade 3; 1, grade 4; 4, grade 5). Dermatologic and neurologic symptoms were common; intratumoral hemorrhage was confirmed in 3 patients. In group 1, 8 of 29 patients (28%) had stable disease with tumor regression approaching 50% in a malignant glioma and an anaplastic oligoastrocytoma. In group 2, overall survival was 12.0 months. EGFR overexpression by immunohistochemistry was found in 17 of 38 (45%) tumor samples analyzed, with a partial gain of 7p11.2 in 1 glioblastoma; phosphate and tensin homolog loss was frequent in brainstem glioma (15 of 19). Mean (95% CI) apparent clearance and volume of distribution for erlotinib were 4.0 L/h (3.4-4.5 L/h) and 98.6 L (69.8-127.0 L), respectively, and were independent of the dose level; mean half-life was 16.6 hours. Thus, erlotinib 125 mg/m² per day has an acceptable tolerability profile in pediatric patients with brain tumors and can be combined with radiotherapy.
Department of Pediatrics, UPRES EA 3535 Pharmacology and New Treatments with Cancer, Institut Gustave Roussy, 94805 Villejuif, France. geoerger@igr.fr
Birgit
B
Geoerger
Darren
D
Hargrave
Fabienne
F
Thomas
Anna
A
Ndiaye
Didier
D
Frappaz
Felipe
F
Andreiuolo
Pascale
P
Varlet
Isabelle
I
Aerts
Riccardo
R
Riccardi
Timothy
T
Jaspan
Etienne
E
Chatelut
Marie-Cecile
MC
Le Deley
Xavier
X
Paoletti
Christian
C
Saint-Rose
Pierre
P
Leblond
Bruce
B
Morland
Jean-Claude
JC
Gentet
Valérie
V
Méresse
Gilles
G
Vassal
D000293:Adolescent; D000328:Adult; D020295:Brain Stem Neoplasms / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D000069347:Erlotinib Hydrochloride; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D007223:Infant; D008297:Male; D020714:Maximum Tolerated Dose; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011799:Quinazolines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015996:Survival Rate; D035703:Therapies, Investigational; D014018:Tissue Distribution; D016896:Treatment Outcome; D055815:Young Adult
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride