Phase I and pharmacokinetic study of gefitinib in children with refractory solid tumors: A children's oncology group study

Purpose: Epidermal growth factor receptor is expressed in pediatric malignant solid tumors. We conducted a phase I trial of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in children with refractory solid tumors. Patients and Methods: Gefitinib (150, 300, 400, or 500 mg/m ²) was administered orally to cohorts of three to six patients once daily continuously until disease progression or significant toxicity. Pharmacokinetic studies were performed during course one (day 1 through 28). Results: Of the 25 enrolled patients, 19 (median age, 15 years) were fully evaluable for toxicity and received 54 courses. Dose-limiting toxicity was rash in two patients treated with 500 mg/m² and elevated ALT and AST in one patient treated with 400 mg/m². The maximum-tolerated dose was 400 mg/m²/d. The most frequent non-dose-limiting toxicities were grade 1 or 2 dry skin, anemia, diarrhea, nausea, and vomiting. One patient with Ewing's sarcoma had a partial response. Disease stabilized for 8 to ≥ 60 weeks in two patients with Wilms' tumor and two with brainstem glioma (one exophytic). At 400 mg/m², the median peak gefitinib plasma concentration was 2.2 μg/mL (range, 1.2 to 3.6 μg/mL) and occurred at a median of 2.3 hours (range, 2.0 to 8.3 hours) after drug administration. The median apparent clearance and median half-life were 14.8 L/h/m² (range, 3.8 to 24.8 L/h/m²) and 11.7 hours (range, 5.6 to 22.8 hours), respectively. Gefitinib systemic exposures were comparable with those associated with antitumor activity in adults. Conclusion: Oral gefitinib is well tolerated in children. Development of the drug in combination with cytotoxic chemotherapy will be pursued.