Phase 1/1b study of lonafarnib and temozolomide in patients with recurrent or temozolomide refractory glioblastoma.

摘要: BACKGROUND Lonafarnib is an oral selective farnesyltransferase inhibitor, a class of drugs which have shown activity in preclinical glioma models. Temozolomide (TMZ) alkylating agent that the first-line chemotherapy for glioblastoma. METHODS The current study combined cytotoxic TMZ with cytostatic lonafarnib patients recurrent glioblastoma to establish maximum tolerated dose (MTD) combination and its preliminary efficacy. Three cohorts were studied phase 1 component trial (100 mg twice daily [bid], 150 bid, 200 bid) dose-dense schedule (150 mg/m2 daily) administered alternating weekly schedule. After establishing MTD lonafarnib, subsequent expansion 1b was undertaken evaluate efficacy, primarily measured by 6-month progression-free survival (PFS-6). RESULTS Fifteen enrolled into 20 component. The bid. Among study, 34 eligible progression evaluation 35 evaluable time-to-progression analysis. PFS-6 rate 38% (95% confidence interval [CI] = 22%, 56%) median PFS 3.9 months CI = 2.5, 8.4). disease-specific 13.7 CI = 8.9, 22.1). Hematologic toxicities, particularly lymphopenia, most common grade 3 4 adverse events. There no treatment-related deaths. CONCLUSIONS These results demonstrate can be safely inhibitor this regimen active, although cannot determine relative contributions 2 agents or contribution novel administration Cancer 2013;119:2747–2753. © 2013 American Society.