TY - JOUR
T1 - Phase i dose escalation and pharmacokinetic study of oral gefitinib and irinotecan in children with refractory solid tumors
AU - Brennan, R. C.
AU - Furman, W.
AU - Mao, S.
AU - Wu, J.
AU - Turner, D. C.
AU - Stewart, C. F.
AU - Santana, V.
AU - McGregor, Lisa
N1 - Publisher Copyright:
© 2014 Springer-Verlag Berlin Heidelberg.
PY - 2014/12
Y1 - 2014/12
N2 - Purpose: This phase I study endeavored to estimate the maximum tolerated dose and describe the dose-limiting toxicities (DLTs) of oral irinotecan with gefitinib in children with refractory solid tumors. Methods: Oral irinotecan was administered on days 1-5 and 8-12 with oral gefitinib (fixed dose, 150 mg/m2/day) on days 1-12 of a 21-day course. The escalation with overdose control method guided irinotecan dose escalation (7 dose levels, range 5-40 mg/m2/day). Results: Sixteen of 19 patients were evaluable, with serial pharmacokinetic studies in ten patients. Diagnoses included osteosarcoma (N = 5), neuroblastoma (N = 3), sarcoma (N = 3), and others (N = 5). Patients received a median of two courses (range 1-20), with at least two patients treated on dose levels 2-7. Three patients had five DLTs; the most common being metabolic (hypokalemia, N = 2 and hypophosphatemia, N = 1) at dose levels two (10 mg/m2) and four (20 mg/m2). One patient experienced grade 3 diarrhea (40 mg/m2). Irinotecan bioavailability was 2.5-fold higher when co-administered with gefitinib, while the conversion rate of irinotecan to SN-38 lactone was unaffected. The study closed due to poor accrual before evaluation of the next recommended irinotecan dose level (35 mg/m2). Of 11 patients receiving at least two courses of therapy, three had stable disease lasting two to four courses and one patient maintained a complete response through 18 courses. Conclusions: The combination of oral gefitinib and irinotecan has acceptable toxicity and anti-tumor activity in pediatric patients with refractory solid tumors. Pharmacokinetic analysis confirms that co-administration of gefitinib increases irinotecan bioavailability leading to an increased SN-38 lactone systemic exposure.
AB - Purpose: This phase I study endeavored to estimate the maximum tolerated dose and describe the dose-limiting toxicities (DLTs) of oral irinotecan with gefitinib in children with refractory solid tumors. Methods: Oral irinotecan was administered on days 1-5 and 8-12 with oral gefitinib (fixed dose, 150 mg/m2/day) on days 1-12 of a 21-day course. The escalation with overdose control method guided irinotecan dose escalation (7 dose levels, range 5-40 mg/m2/day). Results: Sixteen of 19 patients were evaluable, with serial pharmacokinetic studies in ten patients. Diagnoses included osteosarcoma (N = 5), neuroblastoma (N = 3), sarcoma (N = 3), and others (N = 5). Patients received a median of two courses (range 1-20), with at least two patients treated on dose levels 2-7. Three patients had five DLTs; the most common being metabolic (hypokalemia, N = 2 and hypophosphatemia, N = 1) at dose levels two (10 mg/m2) and four (20 mg/m2). One patient experienced grade 3 diarrhea (40 mg/m2). Irinotecan bioavailability was 2.5-fold higher when co-administered with gefitinib, while the conversion rate of irinotecan to SN-38 lactone was unaffected. The study closed due to poor accrual before evaluation of the next recommended irinotecan dose level (35 mg/m2). Of 11 patients receiving at least two courses of therapy, three had stable disease lasting two to four courses and one patient maintained a complete response through 18 courses. Conclusions: The combination of oral gefitinib and irinotecan has acceptable toxicity and anti-tumor activity in pediatric patients with refractory solid tumors. Pharmacokinetic analysis confirms that co-administration of gefitinib increases irinotecan bioavailability leading to an increased SN-38 lactone systemic exposure.
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U2 - 10.1007/s00280-014-2593-7
DO - 10.1007/s00280-014-2593-7
M3 - Article
C2 - 25257509
AN - SCOPUS:84921936137
SN - 0344-5704
VL - 74
SP - 1191
EP - 1198
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 6
ER -