Patients with multiple myeloma (MM) with mutated RAS are less likely to respond to chemotherapy and have a shortened survival. Therefore, targeting RAS farnesylation may be a novel approach to treatment of MM. We evaluated the activity and tolerability of the farnesyltransferase (FTase) inhibitor tipifarnib (Zarnestra) in a phase 2 trial as well as its ability to inhibit protein farnesylation and oncogenic pathways in patients with relapsed MM.

R115777 is a potent farnesyltransferase (FTase) inhibitor with substantial antitumor activity in preclinical models. We conducted a phase 1 study (3 ؉ 3 design) of R115777 in patients with myelodysplastic syndrome (MDS). R115777 was administered twice daily (3-weeks-on/1-weekoff schedule for 8 weeks) (starting dosage, 300 mg by mouth twice daily; total, 600 mg). Maintenance therapy at the dose/ schedule tolerated during induction could be continued until toxicity or lack of benefit. Twenty-one patients with MDS were treated (median age, 66 years). Four (19%) patients had ras mutations (n-ras, 3; k-ras, 1). Objective responses (hematologic improvement, 3; partial remission, 2; or complete remission, 1) were seen in 6 of 20 (30%) evaluable patients, only 2 of whom had ras mutations. Response sequences were unusual in some patients who had increases in platelet counts without intervening aplasia. Other responders demonstrated an initial, albeit modest, myelosuppressive effect. The maximum tolerated dose was 400 mg by mouth twice a day. The most frequent side effect was myelosuppression. Dose-limiting toxicities (fatigue and confusion) occurred at 900 mg by mouth total daily dose. R115777 inhibited HDJ-2 prenylation and suppressed the activity of FTase, but not of the related geranylgeranyltransferase I enzyme, in peripheral blood mononuclear cells. Modulation of Akt, Erk, and signal transducer and activator of transcription 3 (STAT3) phosphorylation was variable, and responses occurred even without their down-regulation. Reductions in serum tumor necrosis factor-␣ (TNF-␣) levels by day 7 showed a trend toward correlation with response (P ‫؍‬ .09). We conclude that, at doses that are well tolerated, R115777 markedly inhibits the FTase target and has antitumor activity in MDS.