In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 25, No. 21 ( 2007-07-20), p. 3137-3143
Kurzfassung:
A dose-escalation phase I and pharmacokinetic study of the farnesyltransferase inhibitor lonafarnib ( SCH66336 ) was conducted in children with recurrent or progressive CNS tumors. Primary objectives were to estimate the maximum-tolerated dose (MTD) and to describe the dose-limiting toxicities (DLTs) and pharmacokinetics of lonafarnib. Farnesylation inhibition of HDJ-2 in peripheral blood was also measured. Patients and Methods Lonafarnib was administered orally twice daily at dose levels of 70, 90, 115, 150, and 200 mg/m 2 /dose bid. A modified continual reassessment method (CRM) was used to estimate the MTD based on actual dosages of lonafarnib administered and toxicities observed during the initial 4 weeks of treatment. Results Fifty-three children with progressive or recurrent brain tumors were enrolled, with a median age of 12.2 years (range, 3.9 to 19.5 years). Dose-limiting pneumonitis or myelosuppression was observed in three of three patients at the 200 mg/m 2 /dose level. A relatively constant DLT rate at the 70, 90, and 115 mg/m 2 /dose levels resulted in a recommended phase II dose of 115 mg/m 2 /dose. Significant diarrhea did not occur with prophylactic loperamide. Both radiographic response (one anaplastic astrocytoma) and stable disease (one medulloblastoma, two high-grade and four low-grade gliomas, one ependymoma, and one sarcoma) were noted, and seven patients remained on treatment for 1 year or longer. Conclusion Although the estimated MTD by the CRM model was 98.5 mg/m 2 /dose, because of the relatively constant observed DLT rate at the lower four dose levels, the recommended phase II dose of lonafarnib is 115 mg/m 2 /dose administered twice daily by mouth with concurrent loperamide.
Materialart:
Online-Ressource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2006.09.4243
Sprache:
Englisch
Verlag:
American Society of Clinical Oncology (ASCO)
Publikationsdatum:
2007
ZDB Id:
2005181-5