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

  • PHASE II STUDIES
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Summary

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.

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Acknowledgments

We thank Sharon Naron for editorial assistance.

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.

Presented in part at Advances in Neuroblastoma Research, Stockholm, Sweden, June, 2010.

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Author notes

  1. Mihaela Onciu

    Present address: OncoMetrix, Memphis, TN, USA

Authors and Affiliations

  1. Department of Oncology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA

    Wayne L. Furman, Lisa M. McGregor, Sandy Kovach & Victor M. Santana

  2. Department of Radiological Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA

    M. Beth McCarville

  3. Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Mihaela Onciu

  4. Department of Surgery, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Andrew M. Davidoff

  5. Department of Cancer Center Administration, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Dana Hawkins & Valerie McPherson

  6. Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Clinton F. Stewart

  7. Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Catherine A. Billups & Jianrong Wu

  8. Department of Pediatrics, The University of Tennessee-Memphis Health Science Center, Memphis, TN, USA

    Wayne L. Furman, Lisa M. McGregor, Andrew M. Davidoff, Clinton F. Stewart & Victor M. Santana

  9. Department of Surgery, The University of Tennessee-Memphis Health Science Center, Memphis, TN, USA

    Andrew M. Davidoff

  10. Center for Childhood Cancer, Nationwide Children’s Hospital, Columbus, OH, USA

    Peter J. Houghton

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Furman, W.L., McGregor, L.M., McCarville, M.B. et al. A single-arm pilot phase II study of gefitinib and irinotecan in children with newly diagnosed high-risk neuroblastoma. Invest New Drugs 30, 1660–1670 (2012). https://doi.org/10.1007/s10637-011-9724-3

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