Pediatric phase I and pharmacokinetic study of erlotinib followed by the combination of erlotinib and temozolomide: a Children's Oncology Group Phase I Consortium Study.
OBJECTIVE
We conducted a phase I and pharmacokinetic study of the epidermal growth factor receptor (EGFR) inhibitor erlotinib as a single agent and in combination with temozolomide in children with refractory solid tumors.


METHODS
Erlotinib was administered orally once daily to cohorts of three to six children for a single 28-day course. Patients then received the combination of daily erlotinib and temozolomide daily for 5 days for all subsequent 28-day courses. An oral erlotinib solution was administered during the dose-finding phase and a tablet formulation was subsequently studied at the maximum-tolerated dose (MTD). Pharmacokinetic studies and ERBB-receptor expression and signaling studies were performed.


RESULTS
Forty-six patients, median age 11.5 years, received erlotinib at doses of 35, 50, 65, 85, or 110 mg/m(2)/d. At 110 mg/m(2)/d, two of four patients had dose-limiting toxicity (DLT) consisting of rash and hyperbilirubinemia, whereas one of six patients developed dose-limiting rash at 85 mg/m(2)/d. The most frequent non-DLTs included diarrhea, rash, and hyperbilirubinemia. The combination of erlotinib and temozolomide was well tolerated. The median apparent erlotinib clearance was 3.1 L/h/m(2) and the median terminal half-life was 8.7 hours. One patient with a neurocytoma had stable disease for 19 months, two patients with neuroblastoma remained on study for 23 and 24 months, and one patient with myoepithelioma had a mixed response.


CONCLUSIONS
The recommended phase II dose of erlotinib in recurrent pediatric solid tumors is 85 mg/m(2)/d, either alone or in combination with temozolomide.
Jakacki
Regina I
RI
Children's Hospital of Pittsburgh, Pittsburgh, PA 15213, USA. regina.jakacki@chp.edu
Hamilton
Marta
M
Gilbertson
Richard J
RJ
Blaney
Susan M
SM
Tersak
Jean
J
Krailo
Mark D
MD
Ingle
Ashish M
AM
Voss
Stephan D
SD
Dancey
Janet E
JE
Adamson
Peter C
PC
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000633:toxicity*; D019540:Area Under Curve; D001859:Bone Neoplasms / Q000188:drug therapy; D001932:Brain Neoplasms / Q000188:drug therapy; D002648:Child; D002675:Child, Preschool; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D003967:Diarrhea / Q000139:chemically induced; D003875:Drug Eruptions / Q000209:etiology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D006801:Humans; D020714:Maximum Tolerated Dose; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy; D009447:Neuroblastoma / Q000188:drug therapy; D012516:Osteosarcoma / Q000188:drug therapy; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D012208:Rhabdomyosarcoma / Q000188:drug therapy; D000077204:Temozolomide
D011799:Quinazolines; D003606:Dacarbazine; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077204:Temozolomide
Drug Metab Dispos. 2006 Mar;34(3):420-6
16381666
Anticancer Drugs. 2004 Jun;15(5):503-12
15166626
J Clin Oncol. 2007 May 20;25(15):1960-6
17452677
Cancer Res. 1997 Nov 1;57(21):4838-48
9354447
J Clin Oncol. 2006 Nov 20;24(33):5259-64
17114659
Clin Pharmacol Ther. 2006 Aug;80(2):136-45
16890575
Neuro Oncol. 2006 Jan;8(1):67-78
16443950
Pharmacol Ther. 1999 May-Jun;82(2-3):241-50
10454201
Clin Cancer Res. 2000 Mar;6(3):998-1007
10741727
Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):795-805
15701870
Cancer. 2007 Oct 1;110(7):1542-50
17705175
Clin Cancer Res. 2000 May;6(5):2053-63
10815932
Cancer Cell. 2007 Jan;11(1):69-82
17222791
BMC Cancer. 2005 Oct 11;5:131
16219105
Cancer Res. 2000 Dec 15;60(24):6841-5
11156376
Biochem Biophys Res Commun. 1999 Feb 24;255(3):774-7
10049786
Cancer Res. 1995 Jul 1;55(13):2853-7
7796412
J Clin Oncol. 2005 Sep 1;23(25):5892-9
16043829
J Clin Oncol. 2001 Jul 1;19(13):3267-79
11432895
Oncologist. 2005 Aug;10(7):508-17
16079318
Clin Cancer Res. 1999 Jul;5(7):1786-92
10430083
Clin Cancer Res. 2007 Jul 1;13(13):3913-21
17606725
J Natl Cancer Inst. 2000 Feb 2;92(3):205-16
10655437
Cancer Res. 2007 Feb 1;67(3):1228-38
17283159
Med Pediatr Oncol. 1995 Feb;24(2):104-8
7990757
Cancer Res. 1996 Sep 1;56(17):3898-901
8752155