Alternate Week Administration of the Farnesyltransferase Inhibitor Tipifarnib (ZARNESTRA^®, R115777) in Patients with Myelodysplastic Syndrome: Results of a Phase 1 Study.

Tipifarnib (ZARNESTRA^®, R115777), an oral selective inhibitor of farnesyltransferase (FTase), demonstrates potent antiangiogenic, antiproliferative, and apoptotic effects. This phase 1 study assessed the tolerability and response rate in patients with myelodysplastic syndrome (MDS) receiving tipifarnib on an alternate week (1 week on/1 week off) schedule. Starting dose of tipifarnib was 100 mg BID, for a total initial treatment period of 8 weeks, with a standard 3+3 design. Dose escalation was 100 mg PO BID until grade 2 nonhematologic toxicity was observed, then 100 mg total dose per day escalation until the maximum tolerated dose (MTD) was reached. Sixty-three patients were treated (median age 68 years; range, 35–84 years) with RA (n = 15), RARS (n = 6), RAEB (n = 26), RAEB-t (n = 8), and CMMoL (n = 8). Five patients (8%) had IPSS score low, 27 (43%) INT-1, 23 (36%) INT-2, and 8 (13%) high. Three patients had an N-Ras mutation and one had a K-Ras mutation. A total of 63 patients were evaluable for toxicity and 61 were evaluable for response (1 noncompliant, 1 ineligible). This alternate week regimen of tipifarnib was well tolerated; the most common toxicity was myelosuppression (all grades, 60% of patients). No side effects were reported by 20% of patients. Nonhematologic toxicities (all grades) included fatigue (20%), skin rash (9%), diarrhea (16%), increase in SGPT (14%), increase in bilirubin (11%), and nausea (11%). Dose-limiting toxicities of ataxia (n = 1), insomnia (n = 1), fatigue (n = 1), nausea (n = 1), and neutropenic fever (n = 2) occurred at tipifarnib 1,300 mg/day to 1,500 mg/day. The MTD of tipifarnib in this patient population was 1,200 mg/day. Fifteen of 61 (25%) evaluable patients responded (3 CRs and 12 hematologic improvements). Major platelet responses were most common; they were observed in 11 of 15 responders. There was no obvious dose-response relationship and three of the fifteen patients (20%) at the lowest dose level (100 mg bid) responded including one CR. Only one patient among the responders (hematologic improvement) had a Ras (N-Ras) mutation. Median time to response was eight weeks (range, 4–32 weeks). In conclusion, an alternate week regimen of tipifarnib was well tolerated and a response rate of 25% was achieved in this phase 1 study in MDS patients. Responses were seen at all dose levels, and major platelet responses were most common. This schedule is therefore conducive to combination regimens as well as to maintenance therapy.