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/m(2) and elevated ALT and AST in one patient treated with 400 mg/m(2). The maximum-tolerated dose was 400 mg/m(2)/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/m(2), the median peak gefitinib plasma concentration was 2.2 mu g/mL (range, 1.2 to 3.6 mu g/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/m(2) (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.