Phase I Study Using Alternate Week Administration of the Farnesyl Transferase Inhibitor R115777 (Zarnestra™) in Patients with Myelodysplastic Syndrome.

R115777 is an oral selective inhibitor of farnesyltransferase with potent antiangiogenic, antiproliferative, and apoptotic effects. The current study assesses the tolerance and response rate in patients (pts) with myelodysplastic syndrome (MDS) receiving R115777 on a one-week on/one-week off schedule. Starting dose was 100 mg bid with a standard 3+3 design for a total initial treatment period of eight weeks. Escalation was 100 mg po bid until grade 2 non-hematologic toxicity was observed, then 100 mg total dose per day escalation until MTD. Fifty-three pts were treated (median age 68.5 yrs; range 35–83) with RA (n=12), RARS (n=4), RAEB (n=22), RAEBt (n=7), and CMMoL (n=8). Three pts (5%) had IPSS score low; 24 (45%), INT-1; 19 (36%), INT-2; and 7 (13%) high score. Three patients had an N-RAS mutation and one had a K-RAS mutation. Fifty-three patients are evaluable for toxicity and 51 are evaluable for response (1 non-compliant, 1 ineligible). This regimen was well tolerated. The most common toxicity was myelosuppression (60% of the patients). Twenty percent reported no side effects. Non-hematologic toxicities included mild skin rash (15%), diarrhea (13%), increase in SGPT (13%), increase in bilirubin (10%), and nausea (8%). DLTs of ataxia (n=1) and fatigue (n=1) occurred at doses of 1300 mg/day. The MTD appears to be 1200 mg/day. Fifteen of 51 evaluable patients responded (3 CRs and 12 hematologic improvements). Interestingly, 3 of 6 pts at the lowest dose level (100 mg bid) responded, including a CR. Major platelet responses were most common; 11 of the 15 responders had a platelet response. Only one patient among the responders (hematologic improvement) had a RAS (N-RAS) mutation. Median time to response is eight weeks (range: 4–32 weeks). In conclusion, alternate week therapy with R115777 is well tolerated and a response rate of 29% is achieved in the Phase I setting. This intermittent schedule would lend itself well to combination or maintenance regimens.