Tyrosine kinase inhibitor enhances the bioavailability of oral irinotecan in pediatric patients with refractory solid tumors

Wayne L. Furman, Fariba Navid, Najat C. Daw, M. Beth McCarville, Lisa McGregor, Sheri L. Spunt, Carlos Rodriguez-Galindo, John C. Panetta, Kristine R. Crews, Jianrong Wu, Amar J. Gajjar, Peter J. Houghton, Victor M. Santana, Clinton F. Stewart

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Abstract

Purpose: To assess the maximum-tolerated dosages (MTDs), and dose-limiting toxicities (DLTs) of the epidermal growth factor receptor inhibitor gefitinib and of intravenous (IV) irinotecan when administered together in children with refractory solid tumors. To assess the effect of gefitinib on the pharmacokinetics of IV irinotecan and on the bioavailability of a single oral dose of irinotecan. Patients and Methods: IV irinotecan (15 or 20 mg/m 2) was given daily for 5 days of 2 consecutive weeks. Oral gefitinib (150 or 112.5 mg/m2) was concomitantly given daily for 12 or 21 days. A single oral dose of irinotecan was given on day 9 of course 2 to allow pharmacokinetic analysis. Results: The study enrolled 29 patients with recurrent solid tumors. The 21-day regimen of oral gefitinib with irinotecan was not tolerated. Diarrhea was the most common DLT. The MTD of the combination regimen was 15 mg/m2/d of IV irinotecan for 5 days of 2 consecutive weeks and 112.5 mg/m2/d of gefitinib given for 12 days. Gefitinib increased the bioavailability of oral irinotecan by four-fold over that observed in historical controls (median, 0.09 v 0.42; P < .000001), reducing the apparent clearance (an inverse measure of exposure) of irinotecan and SN-38 by 37% and 38%, respectively (P < .0001). A partial response was observed in a patient with refractory Ewing sarcoma. Conclusion: IV irinotecan given with 12 days of oral gefitinib is well tolerated in children. We observed one partial response. Gefitinib significantly enhances the bioavailability of oral irinotecan. This combination warrants further investigation, particularly with orally administered irinotecan.

Original languageEnglish (US)
Pages (from-to)4599-4604
Number of pages6
JournalJournal of Clinical Oncology
Volume27
Issue number27
DOIs
StatePublished - Sep 20 2009

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irinotecan
Protein-Tyrosine Kinases
Biological Availability
Pediatrics
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Furman, Wayne L. ; Navid, Fariba ; Daw, Najat C. ; Beth McCarville, M. ; McGregor, Lisa ; Spunt, Sheri L. ; Rodriguez-Galindo, Carlos ; Panetta, John C. ; Crews, Kristine R. ; Wu, Jianrong ; Gajjar, Amar J. ; Houghton, Peter J. ; Santana, Victor M. ; Stewart, Clinton F. / Tyrosine kinase inhibitor enhances the bioavailability of oral irinotecan in pediatric patients with refractory solid tumors. In: Journal of Clinical Oncology. 2009 ; Vol. 27, No. 27. pp. 4599-4604.
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title = "Tyrosine kinase inhibitor enhances the bioavailability of oral irinotecan in pediatric patients with refractory solid tumors",
abstract = "Purpose: To assess the maximum-tolerated dosages (MTDs), and dose-limiting toxicities (DLTs) of the epidermal growth factor receptor inhibitor gefitinib and of intravenous (IV) irinotecan when administered together in children with refractory solid tumors. To assess the effect of gefitinib on the pharmacokinetics of IV irinotecan and on the bioavailability of a single oral dose of irinotecan. Patients and Methods: IV irinotecan (15 or 20 mg/m 2) was given daily for 5 days of 2 consecutive weeks. Oral gefitinib (150 or 112.5 mg/m2) was concomitantly given daily for 12 or 21 days. A single oral dose of irinotecan was given on day 9 of course 2 to allow pharmacokinetic analysis. Results: The study enrolled 29 patients with recurrent solid tumors. The 21-day regimen of oral gefitinib with irinotecan was not tolerated. Diarrhea was the most common DLT. The MTD of the combination regimen was 15 mg/m2/d of IV irinotecan for 5 days of 2 consecutive weeks and 112.5 mg/m2/d of gefitinib given for 12 days. Gefitinib increased the bioavailability of oral irinotecan by four-fold over that observed in historical controls (median, 0.09 v 0.42; P < .000001), reducing the apparent clearance (an inverse measure of exposure) of irinotecan and SN-38 by 37{\%} and 38{\%}, respectively (P < .0001). A partial response was observed in a patient with refractory Ewing sarcoma. Conclusion: IV irinotecan given with 12 days of oral gefitinib is well tolerated in children. We observed one partial response. Gefitinib significantly enhances the bioavailability of oral irinotecan. This combination warrants further investigation, particularly with orally administered irinotecan.",
author = "Furman, {Wayne L.} and Fariba Navid and Daw, {Najat C.} and {Beth McCarville}, M. and Lisa McGregor and Spunt, {Sheri L.} and Carlos Rodriguez-Galindo and Panetta, {John C.} and Crews, {Kristine R.} and Jianrong Wu and Gajjar, {Amar J.} and Houghton, {Peter J.} and Santana, {Victor M.} and Stewart, {Clinton F.}",
year = "2009",
month = "9",
day = "20",
doi = "10.1200/JCO.2008.19.6642",
language = "English (US)",
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journal = "Journal of Clinical Oncology",
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Furman, WL, Navid, F, Daw, NC, Beth McCarville, M, McGregor, L, Spunt, SL, Rodriguez-Galindo, C, Panetta, JC, Crews, KR, Wu, J, Gajjar, AJ, Houghton, PJ, Santana, VM & Stewart, CF 2009, 'Tyrosine kinase inhibitor enhances the bioavailability of oral irinotecan in pediatric patients with refractory solid tumors', Journal of Clinical Oncology, vol. 27, no. 27, pp. 4599-4604. https://doi.org/10.1200/JCO.2008.19.6642

Tyrosine kinase inhibitor enhances the bioavailability of oral irinotecan in pediatric patients with refractory solid tumors. / Furman, Wayne L.; Navid, Fariba; Daw, Najat C.; Beth McCarville, M.; McGregor, Lisa; Spunt, Sheri L.; Rodriguez-Galindo, Carlos; Panetta, John C.; Crews, Kristine R.; Wu, Jianrong; Gajjar, Amar J.; Houghton, Peter J.; Santana, Victor M.; Stewart, Clinton F.

In: Journal of Clinical Oncology, Vol. 27, No. 27, 20.09.2009, p. 4599-4604.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Tyrosine kinase inhibitor enhances the bioavailability of oral irinotecan in pediatric patients with refractory solid tumors

AU - Furman, Wayne L.

AU - Navid, Fariba

AU - Daw, Najat C.

AU - Beth McCarville, M.

AU - McGregor, Lisa

AU - Spunt, Sheri L.

AU - Rodriguez-Galindo, Carlos

AU - Panetta, John C.

AU - Crews, Kristine R.

AU - Wu, Jianrong

AU - Gajjar, Amar J.

AU - Houghton, Peter J.

AU - Santana, Victor M.

AU - Stewart, Clinton F.

PY - 2009/9/20

Y1 - 2009/9/20

N2 - Purpose: To assess the maximum-tolerated dosages (MTDs), and dose-limiting toxicities (DLTs) of the epidermal growth factor receptor inhibitor gefitinib and of intravenous (IV) irinotecan when administered together in children with refractory solid tumors. To assess the effect of gefitinib on the pharmacokinetics of IV irinotecan and on the bioavailability of a single oral dose of irinotecan. Patients and Methods: IV irinotecan (15 or 20 mg/m 2) was given daily for 5 days of 2 consecutive weeks. Oral gefitinib (150 or 112.5 mg/m2) was concomitantly given daily for 12 or 21 days. A single oral dose of irinotecan was given on day 9 of course 2 to allow pharmacokinetic analysis. Results: The study enrolled 29 patients with recurrent solid tumors. The 21-day regimen of oral gefitinib with irinotecan was not tolerated. Diarrhea was the most common DLT. The MTD of the combination regimen was 15 mg/m2/d of IV irinotecan for 5 days of 2 consecutive weeks and 112.5 mg/m2/d of gefitinib given for 12 days. Gefitinib increased the bioavailability of oral irinotecan by four-fold over that observed in historical controls (median, 0.09 v 0.42; P < .000001), reducing the apparent clearance (an inverse measure of exposure) of irinotecan and SN-38 by 37% and 38%, respectively (P < .0001). A partial response was observed in a patient with refractory Ewing sarcoma. Conclusion: IV irinotecan given with 12 days of oral gefitinib is well tolerated in children. We observed one partial response. Gefitinib significantly enhances the bioavailability of oral irinotecan. This combination warrants further investigation, particularly with orally administered irinotecan.

AB - Purpose: To assess the maximum-tolerated dosages (MTDs), and dose-limiting toxicities (DLTs) of the epidermal growth factor receptor inhibitor gefitinib and of intravenous (IV) irinotecan when administered together in children with refractory solid tumors. To assess the effect of gefitinib on the pharmacokinetics of IV irinotecan and on the bioavailability of a single oral dose of irinotecan. Patients and Methods: IV irinotecan (15 or 20 mg/m 2) was given daily for 5 days of 2 consecutive weeks. Oral gefitinib (150 or 112.5 mg/m2) was concomitantly given daily for 12 or 21 days. A single oral dose of irinotecan was given on day 9 of course 2 to allow pharmacokinetic analysis. Results: The study enrolled 29 patients with recurrent solid tumors. The 21-day regimen of oral gefitinib with irinotecan was not tolerated. Diarrhea was the most common DLT. The MTD of the combination regimen was 15 mg/m2/d of IV irinotecan for 5 days of 2 consecutive weeks and 112.5 mg/m2/d of gefitinib given for 12 days. Gefitinib increased the bioavailability of oral irinotecan by four-fold over that observed in historical controls (median, 0.09 v 0.42; P < .000001), reducing the apparent clearance (an inverse measure of exposure) of irinotecan and SN-38 by 37% and 38%, respectively (P < .0001). A partial response was observed in a patient with refractory Ewing sarcoma. Conclusion: IV irinotecan given with 12 days of oral gefitinib is well tolerated in children. We observed one partial response. Gefitinib significantly enhances the bioavailability of oral irinotecan. This combination warrants further investigation, particularly with orally administered irinotecan.

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DO - 10.1200/JCO.2008.19.6642

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