Phase I and pharmacokinetic study of gefitinib in children with refractory solid tumors: a Children's Oncology Group Study.

Abstract

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/m2) 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 > or = 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 microg/mL (range, 1.2 to 3.6 microg/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.

• Authors: Najat C Daw, Wayne L Furman, Clinton F Stewart, Lisa C Iacono, Mark Krailo, Mark L Bernstein, Janet E Dancey, Rose Anne Speights, Susan M Blaney, James M Croop, Gregory H Reaman, Peter C Adamson, Children's Oncology Group
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 23 Issue 25 Pg. 6172-80 (Sep 01 2005) ISSN: 0732-183X [Print] United States
• PMID: 16135484 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Quinazolines
• ErbB Receptors
• Gefitinib

Topics

• Administration, Oral
• Adolescent
• Adult
• Age Factors
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Child
• Child, Preschool
• ErbB Receptors (antagonists & inhibitors)
• Female
• Gefitinib
• Humans
• Infant
• Male
• Neoplasms (drug therapy)
• Quinazolines (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Treatment Outcome