J Clin Oncol. 2005 Sep 1;23(25):6172-6180.
Phase I and Pharmacokinetic Study of Gefitinib in Children With
Refractory Solid Tumors: A Children's Oncology Group Study.
Daw NC, Furman WL, Stewart CF, Iacono LC, Krailo M, Bernstein ML,
Dancey JE, Speights RA, Blaney SM, Croop JM, Reaman GH, Adamson PC.
Department of Hematology-Oncology, Mail Stop 260, St Jude
Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794;
e-mail: najat.daw@stjude.org.
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 mug/mL (range, 1.2 to 3.6 mug/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/m(2)) 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.
PMID: 16135484 [PubMed – as supplied by publisher]