In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 28, No. 27 ( 2010-09-20), p. 4221-4227
Kurzfassung:
To estimate the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetic properties of lapatinib, a selective epidermal growth factor receptor (EGFR) and ERBB2 inhibitor, in children with refractory or recurrent CNS malignancies. Patients and Methods Lapatinib was administered orally twice daily at escalating doses starting at 300 mg/m 2 to patients who were not (stratum I) or were (stratum II) receiving steroids. Pharmacokinetic studies were performed during the first two courses. Expression of the four ERBB receptors and downstream signaling elements in tumor tissue was evaluated by immunohistochemistry. Results Fifty-nine patients were enrolled (stratum I, n = 32; stratum II, n = 27). Of 29 patients evaluable for toxicity in stratum I, one experienced a DLT (diarrhea) at 520 mg/m 2 twice daily, and all three receiving 1,150 mg/m 2 twice daily experienced DLTs (one each of rash, diarrhea, and fatigue). Two of 21 patients evaluable for toxicity in stratum II experienced DLTs of rash at 900 mg/m 2 twice daily. Lapatinib dosage was related linearly to area under the [concentration-time] curve from start time to 12 hours later (AUC 0-12 ) and dose-normalized maximum serum concentration and AUC values for patients in stratum II were both significantly higher (P = .001) than those for patients in stratum I. Frequent, high-level expression of activated (phosphorylated) EGFR and ERBB2 receptors and downstream signal intermediates were observed in tumors, particularly in ependymomas that displayed prolonged stable disease on lapatinib therapy. Conclusion Lapatinib is well tolerated in children with recurrent CNS malignancies, with rash, diarrhea, and fatigue identified as DLTs. The recommended phase II dose, regardless of steroid use, is 900 mg/m 2 twice daily.
Materialart:
Online-Ressource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2010.28.4687
Sprache:
Englisch
Verlag:
American Society of Clinical Oncology (ASCO)
Publikationsdatum:
2010
ZDB Id:
2005181-5
