Phase I evaluation of tipifarnib in combination with low-dose Ara-C (LDAC) in high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML): Interim results

Abstract

14014 Background: Tipifarnib (T) is a farnesyltransferase inhibitor with clinical activity in MDS and AML. LDAC has utility in the elderly with MDS/AML; hence its use in combination with the investigational agent T to improve outcomes is warranted. Methods: The primary objective of this ongoing phase I, dose finding, multicenter, open-label study was to determine the maximum tolerated dose (MTD) based on dose limiting toxicities (DLT) of T+LDAC observed during the first 28 day cycle. MDS (IPSS Int 1, 2 or High) and untreated AML pts (age =75y or =65y with preceding MDS) or relapsed/refractory AML (age >18y) were included. Planned sample size was up to 57 pts with a traditional 3+3 dose escalation and a minimum of 3 pts enrolled per cohort. T (Dose Level 0) was administered initially at 200mg PO BID x 21 days in combination with LDAC 10mg SC BID x 10 days; both repeated every 28 days. Efficacy will be assessed by bone marrow and peripheral blood count studies. Results: 15 pts have been enrolled to date: 2 MDS (Int 1 n=1, High n=1) and 13 AML (7/13 pts with no previous therapy); all 15 pts were evaluable. Mean baseline characteristics for the entire cohort were: age 76.2y, 67% men, Hb 9.4 ± 0.9 g/dL, WBC 8.7 ± 11.3 x 103/μL, platelets 96.8 ± 96.6 x 103/μL. The observed DLT for T+LDAC was generalized rash seen at Dose Level 3. The MTD was therefore determined to be T 300mg and LDAC 15mg. The most common grade 3/4 adverse events were neutropenia, thrombocytopenia, anemia, and rash. Conclusions: These interim findings show the combination of T at 300mg PO BID x 21 days and LDAC at 15mg SC BID x 10 days to be the MTD in this study. Assessment for efficacy is ongoing. [Table: see text] No significant financial relationships to disclose.