A single-arm pilot phase II study of gefitinib and irinotecan in children with newly diagnosed high-risk neuroblastoma

Wayne L. Furman, Lisa M. McGregor, M. Beth McCarville, Mihaela Onciu, Andrew M. Davidoff, Sandy Kovach, Dana Hawkins, Valerie McPherson, Peter J. Houghton, Catherine A. Billups, Jianrong Wu, Clinton F. Stewart, Victor M. Santana

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


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/m2/day (daily ×5)×2] were combined with 12 daily doses of gefitinib (112.5 mg/m2/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.

Original languageEnglish
Pages (from-to)1660-1670
Number of pages11
JournalInvestigational New Drugs
Issue number4
StatePublished - Aug 2012

Bibliographical note

Funding Information:
Supported by grants CA23099 and P30 21765 from the NIH and supported in part by a grant from Astra Zeneca. The authors declare no financial conflicts of interest.


  • ATP-binding cassette transporters
  • Clinical trial
  • Gefitinib
  • Irinotecan
  • Neuroblastoma
  • Phase II

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)


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