title: Phase I dose escalation and pharmacokinetic study of oral gefitinib and irinotecan in children with refractory solid tumors.
abstract: OBJECTIVE
  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/m(2)/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/m(2)/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/m(2)) and four (20 mg/m(2)). One patient experienced grade 3 diarrhea (40 mg/m(2)). 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/m(2)). 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.
authors.affiliation: Division of Solid Tumor, Departments of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 260, Memphis, TN, 38105, USA, rachel.brennan@stjude.org.
authors.forename: R C
authors.initials: RC
authors.lastname: Brennan
authors.forename: W
authors.initials: W
authors.lastname: Furman
authors.forename: S
authors.initials: S
authors.lastname: Mao
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.forename: D C
authors.initials: DC
authors.lastname: Turner
authors.forename: C F
authors.initials: CF
authors.lastname: Stewart
authors.forename: V
authors.initials: V
authors.lastname: Santana
authors.forename: L M
authors.initials: LM
authors.lastname: McGregor
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001682:Biological Availability; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D000077156:Gefitinib; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000008:administration & dosage; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D011799:Quinazolines; D000077146:Irinotecan; D000077156:Gefitinib; D002166:Camptothecin