A phase 1-2 study of a farnesyltransferase inhibitor, tipifarnib, combined with idarubicin and cytarabine for patients with newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndrome

BACKGROUND: The authors conducted a phase 1/2 study of tipifarnib in combination with idarubicin and cytarabine (IA) in 95 patients with previously untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome. METHODS: Induction consisted of idarubicin 12 mg/m² a day on days 1-3, cytarabine 1.5 g/m² intravenously continuously daily on days 1-4 (days 1-3 if age ≥60 years), and tipifarnib, with the first cohort (n = 6) receiving 200 mg orally twice a day and all others receiving 300 mg twice a day for 21 days every 28 days. Consolidation consisted of 5 courses of idarubicin 8 mg/m² a day on days 1-2, cytarabine 0.75 g/m² a day on days 1-3, and tipifarnib 300 mg twice a day for 14 days every 4-6 weeks. Maintenance with tipifarnib 300 mg twice a day for 21 days every 4-6 weeks was continued for 6 months. RESULTS: With a median follow-up of 33 months, 61 patients achieved complete remission (CR) (64%), and 9 achieved complete remission with incomplete platelet recovery (CRp) (9%). The median duration of CR was not reached. Median overall survival was 17 months. The most common grade 3 adverse events were gastrointestinal toxicities, liver dysfunction, and skin rash. Compared with historical IA, IA and tipifarnib showed a better CR duration (P =.04) and a trend toward a higher CR rate in patients with chromosome 5/7 abnormalities. CONCLUSIONS: The combination of IA and tipifarnib is safe and active. Further studies exploring different dosages and schedules are warranted, particularly in patients with poor-risk AML.