title: 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.
abstract: 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.
authors.affiliation: Children's Hospital of Pittsburgh, Pittsburgh, PA 15213, USA. regina.jakacki@chp.edu
authors.forename: Regina I
authors.initials: RI
authors.lastname: Jakacki
authors.forename: Marta
authors.initials: M
authors.lastname: Hamilton
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
authors.forename: Jean
authors.initials: J
authors.lastname: Tersak
authors.forename: Mark D
authors.initials: MD
authors.lastname: Krailo
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Ingle
authors.forename: Stephan D
authors.initials: SD
authors.lastname: Voss
authors.forename: Janet E
authors.initials: JE
authors.lastname: Dancey
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
mesh_terms: 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
chemical_list: D011799:Quinazolines; D003606:Dacarbazine; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077204:Temozolomide
references.citation: Drug Metab Dispos. 2006 Mar;34(3):420-6
references.pmid: 16381666
references.citation: Anticancer Drugs. 2004 Jun;15(5):503-12
references.pmid: 15166626
references.citation: J Clin Oncol. 2007 May 20;25(15):1960-6
references.pmid: 17452677
references.citation: Cancer Res. 1997 Nov 1;57(21):4838-48
references.pmid: 9354447
references.citation: J Clin Oncol. 2006 Nov 20;24(33):5259-64
references.pmid: 17114659
references.citation: Clin Pharmacol Ther. 2006 Aug;80(2):136-45
references.pmid: 16890575
references.citation: Neuro Oncol. 2006 Jan;8(1):67-78
references.pmid: 16443950
references.citation: Pharmacol Ther. 1999 May-Jun;82(2-3):241-50
references.pmid: 10454201
references.citation: Clin Cancer Res. 2000 Mar;6(3):998-1007
references.pmid: 10741727
references.citation: Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):795-805
references.pmid: 15701870
references.citation: Cancer. 2007 Oct 1;110(7):1542-50
references.pmid: 17705175
references.citation: Clin Cancer Res. 2000 May;6(5):2053-63
references.pmid: 10815932
references.citation: Cancer Cell. 2007 Jan;11(1):69-82
references.pmid: 17222791
references.citation: BMC Cancer. 2005 Oct 11;5:131
references.pmid: 16219105
references.citation: Cancer Res. 2000 Dec 15;60(24):6841-5
references.pmid: 11156376
references.citation: Biochem Biophys Res Commun. 1999 Feb 24;255(3):774-7
references.pmid: 10049786
references.citation: Cancer Res. 1995 Jul 1;55(13):2853-7
references.pmid: 7796412
references.citation: J Clin Oncol. 2005 Sep 1;23(25):5892-9
references.pmid: 16043829
references.citation: J Clin Oncol. 2001 Jul 1;19(13):3267-79
references.pmid: 11432895
references.citation: Oncologist. 2005 Aug;10(7):508-17
references.pmid: 16079318
references.citation: Clin Cancer Res. 1999 Jul;5(7):1786-92
references.pmid: 10430083
references.citation: Clin Cancer Res. 2007 Jul 1;13(13):3913-21
references.pmid: 17606725
references.citation: J Natl Cancer Inst. 2000 Feb 2;92(3):205-16
references.pmid: 10655437
references.citation: Cancer Res. 2007 Feb 1;67(3):1228-38
references.pmid: 17283159
references.citation: Med Pediatr Oncol. 1995 Feb;24(2):104-8
references.pmid: 7990757
references.citation: Cancer Res. 1996 Sep 1;56(17):3898-901
references.pmid: 8752155