¹Schering-Plough, Dana-Faber Cancer Institute, Kenilworth, NJ

Abstract

Background/aims: Lonafarnib (L, SCH 66336) is an oral farnesyl protein transferase inhibitor (FPTI). Ras mutations or over-expression have been identified in both adult and pediatric brain tumors. Pre-clinical studies have demonstrated that both ras mutant and non-mutated tumors that signal through this pathway can be effectively inhibited by FPTI. In addition to assessment of the dosing-limiting toxicities and maximally tolerated dose (MTD), an objective of this Phase 1 study was to assess the pharmacokinetics (PK) of L in children with brain tumors.

Methods: Patients (n=3-9/dose) received 70 to 150 mg/m² L orally twice daily. Plasma samples were collected and analyzed for plasma L concentrations to assess the multiple-dose PK of L.

Results: Mean (%CV) PK parameters of L are: (Table)

L was safe and well tolerated at doses of 70 to 150 mg/m² in children with brain tumors. lonafarnib is slowly absorbed; median tmax values are 4 hr. increases in L exposure are dose-related.

Conclusions: The PK of L at doses of 115 and 150 mg/m² in children are similar to those at 200 mg (MTD) in adults. Further clinical studies to assess the efficacy of L in pediatric patients with brain tumors are warranted.