TY - JOUR
T1 - Phase I and pharmacokinetic study of the oral farnesyltransferase inhibitor lonafarnib administered twice daily to pediatric patients with advanced central nervous system tumors using a modified continuous reassessment method
T2 - A pediatric brain tumor consortium study
AU - Kieran, Mark W.
AU - Packer, Roger J.
AU - Onar, Arzu
AU - Blaney, Susan M.
AU - Phillips, Peter
AU - Pollack, Ian F.
AU - Geyer, J. Russell
AU - Gururangan, Sri
AU - Banerjee, Anu
AU - Goldman, Stewart
AU - Turner, Christopher D.
AU - Belasco, Jean B.
AU - Broniscer, Alberto
AU - Zhu, Yali
AU - Frank, Emily
AU - Kirschmeier, Paul
AU - Statkevich, Paul
AU - Yver, Antoine
AU - Boyett, James M.
AU - Kun, Larry E.
PY - 2007/7/20
Y1 - 2007/7/20
N2 - Purpose: A dose-escalation phase I and pharmacokinetic study of the famesyltransferase 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/m2/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/m2/dose level. A relatively constant DLT rate at the 70, 90, and 115 mg/m2/dose levels resulted in a recommended phase II dose of 115 mg/m2/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/m2/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/m2/dose administered twice daily by mouth with concurrent loperamide.
AB - Purpose: A dose-escalation phase I and pharmacokinetic study of the famesyltransferase 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/m2/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/m2/dose level. A relatively constant DLT rate at the 70, 90, and 115 mg/m2/dose levels resulted in a recommended phase II dose of 115 mg/m2/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/m2/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/m2/dose administered twice daily by mouth with concurrent loperamide.
UR - http://www.scopus.com/inward/record.url?scp=34547659068&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34547659068&partnerID=8YFLogxK
U2 - 10.1200/JCO.2006.09.4243
DO - 10.1200/JCO.2006.09.4243
M3 - Article
C2 - 17634493
AN - SCOPUS:34547659068
SN - 0732-183X
VL - 25
SP - 3137
EP - 3143
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 21
ER -