A Phase 1 Trial Dose Escalation Study of Tipifarnib on a Week-On, Week-Off Schedule in Relapsed, Refractory or High-Risk Myeloid Leukemia

Inhibition of farnesyltransferase (FT) activity has been associated with in vitro and in vivo anti-leukemia activity. We report the results of a phase 1 dose escalation study of tipifarnib, an oral FT inhibitor, in patients with relapsed, refractory, or newly diagnosed (if over age 70) acute myelogenous leukemia (AML), on a week-on, week-off schedule. Forty-four patients were enrolled, 2 patients were newly diagnosed, the rest were relapsed or refractory to previous treatment, with a median age of 61 (range 33–79). The maximum tolerated dose was determined to be 1200 mg given orally twice-daily (bid) on this schedule. Cycle one dose-limiting toxicities were hepatic and renal. There were 3 complete remissions seen, 2 at the 1200 mg bid dose and one at the 1000 mg bid dose, with minor responses seen at the 1400 mg bid dose level. Pharmacokinetic studies performed at doses of 1400 mg bid showed linear behavior with minimal accumulation between days 1–5. Tipifarnib administered on a week-on week-off schedule shows activity at higher doses, and represents an option for future clinical trials in AML.