title: A single-arm pilot phase II study of gefitinib and irinotecan in children with newly diagnosed high-risk neuroblastoma.
abstract: BACKGROUND
  Gefitinib potently inhibits neuroblastoma proliferation in vitro, and the gefitinib/irinotecan combination shows greater than additive activity against neuroblastoma xenografts. This Phase II pilot study estimated the rate of response to two courses of intravenous irinotecan plus oral gefitinib in children with untreated high-risk neuroblastoma.
  
  
  METHODS
  Two courses of irinotecan [15 mg/m(2)/day (daily ×5)×2] were combined with 12 daily doses of gefitinib (112.5 mg/m(2)/day). Response was assessed after 6 weeks. A response rate >55% was sought.
  
  
  RESULTS
  Of the 23 children enrolled, 19 were evaluable for response. Median age at diagnosis was 3.1 years (range, 18 days-12.7 years). Most patients were older than 24 months (n = 20; 87%), male (n = 18; 78%), white (n = 16; 70%), had INSS 4 disease (n = 19; 83%), and had adrenal primary tumors (n = 18; 78%); nine patients (39%) had amplified tumor MYCN. The toxicity of gefitinib/irinotecan was mild and reversible (nausea, 5/20; diarrhea, 8/20; vomiting, 7/20). Five patients had partial responses; 9 others had a 23%-60% decrease in primary tumor volume and/or improved MIBG scans or decreased bone or bone marrow tumor burden. Median (range) systemic irinotecan exposure (AUC) was 283 ng/ml*hr (range, 163-890 ng/ml*hr) and 28 ng/ml*hr (3.6-297 ng/ml*hr) for the active metabolite, SN-38. No relation was observed between response and tumor expression of EGFR, MRP2-4, ABCG2, and Pgp.
  
  
  CONCLUSIONS
  Although the gefitinib/irinotecan combination was very tolerable and induced responses, it was not sufficiently active to warrant further investigation. Initial investigational studies of this type can preclude the necessity for larger, longer, and costlier trials.
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA. wayne.furman@stjude.org
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Furman
authors.forename: Lisa M
authors.initials: LM
authors.lastname: McGregor
authors.forename: M Beth
authors.initials: MB
authors.lastname: McCarville
authors.forename: Mihaela
authors.initials: M
authors.lastname: Onciu
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davidoff
authors.forename: Sandy
authors.initials: S
authors.lastname: Kovach
authors.forename: Dana
authors.initials: D
authors.lastname: Hawkins
authors.forename: Valerie
authors.initials: V
authors.lastname: McPherson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Billups
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wu
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.forename: Victor M
authors.initials: VM
authors.lastname: Santana
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D005260:Female; D000077156:Gefitinib; D006719:Homovanillic Acid / Q000652:urine; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D000077146:Irinotecan; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism; D009447:Neuroblastoma / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy* / Q000652:urine; D010865:Pilot Projects; D011799:Quinazolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D012307:Risk Factors; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D014642:Vanilmandelic Acid / Q000652:urine
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D011799:Quinazolines; D014642:Vanilmandelic Acid; D000077146:Irinotecan; D007770:L-Lactate Dehydrogenase; D000077156:Gefitinib; D006719:Homovanillic Acid; D002166:Camptothecin