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

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...

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Published in:	Investigational new drugs Vol. 30; no. 4; pp. 1660 - 1670
Main Authors:	Furman, Wayne L., McGregor, Lisa M., McCarville, M. Beth, Onciu, Mihaela, Davidoff, Andrew M., Kovach, Sandy, Hawkins, Dana, McPherson, Valerie, Houghton, Peter J., Billups, Catherine A., Wu, Jianrong, Stewart, Clinton F., Santana, Victor M.
Format:	Journal Article
Language:	English
Published:	Boston Springer US 01-08-2012 Springer Nature B.V
Subjects:	Age Antineoplastic Agents - adverse effects Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Antineoplastic Combined Chemotherapy Protocols - adverse effects Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics Antineoplastic Combined Chemotherapy Protocols - pharmacology Antineoplastic Combined Chemotherapy Protocols - therapeutic use Bone marrow Camptothecin - adverse effects Camptothecin - analogs & derivatives Camptothecin - pharmacokinetics Camptothecin - pharmacology Camptothecin - therapeutic use Cancer therapies Chemotherapy Child Child, Preschool Children & youth Clinical trials Cytotoxicity Drug dosages Drug therapy Female Histology Homovanillic Acid - urine Hospitals Humans Immunohistochemistry Infant Infant, Newborn Inhibitor drugs Kinases L-Lactate Dehydrogenase - blood Male Medicine Medicine & Public Health Neoplasm Proteins - metabolism Neuroblastoma Neuroblastoma - blood Neuroblastoma - diagnosis Neuroblastoma - drug therapy Neuroblastoma - urine Oncology Patients Pharmacology/Toxicology Phase II Studies Pilot Projects Quinazolines - adverse effects Quinazolines - pharmacokinetics Quinazolines - pharmacology Quinazolines - therapeutic use Response rates Risk Factors Science Statistical analysis Treatment Outcome Tumor Burden - drug effects Tumors Vanilmandelic Acid - urine United States > US Irinotecan Clinical trial ATP-binding cassette transporters Phase II Neuroblastoma Gefitinib
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Summary:	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/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/mlhr (range, 163–890 ng/mlhr) and 28 ng/mlhr (3.6–297 ng/mlhr) 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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 Current location: OncoMetrix, Memphis, TN
ISSN:	0167-6997 1573-0646
DOI:	10.1007/s10637-011-9724-3