Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial

R115777 is a nonpeptidomimetic enzyme-specific inhibitor of farnesyl protei n transferase (FT) that was developed as a potential inhibitor of Ras prote in signaling, with antitumor activity in preclinical models, This study was a phase 1 trial of orally administered R115777 in 35 adults with poor-risk acute leukemias. Cohorts of patients received R115777 at doses ranging fro m 100 mg twice daily (bid) to 1200 mg bid for up to 21 days, Dose-limiting toxicity occurred at 1200 mg bid, with central neurotoxicity evidenced by a taxia, confusion, and dysarthria, Non-dose-limiting toxicities included rev ersible nausea, renal insufficiency, polydipsia, paresthesias, and myelosup pression, R115777 inhibited FT activity at 300 mg bid and farnesylation of FT substrates lamin A and HDJ-2 at 600 mg bid, Extracellular signal-regulat ed kinase (ERK), an effector enzyme of Ras-mediated signaling, was detected in its phosphorylated (activated) form in 8 (36.4%) of 22 pretreatment mar rows and became undetectable in 4 of those 8 after one cycle of treatment. Pharmacokinetics revealed a linear relationship between dose and maximum pl asma concentration or area under the curve over 12 hours at all dose levels . Weekly marrow samples demonstrated that R115777 accumulated in bone marro w in a dose-dependent fashion, with large increases in marrow drug levels b eginning at 600 mg bid and with sustained levels throughout drug administra tion, Clinical responses occurred in 10 (29%) of the 34 evaluable patients, including 2 complete remissions, Genomic analyses failed to detect N-ras g ene mutations in any of the 35 leukemias, The results of this first clinica l trial of a signal transduction inhibitor in patients with acute leukemias suggest that inhibitors of FT may have important clinical antileukemic act ivity. (Blood, 2001;97:3361-3369) (C) 2001 by The American Society of Hemat ology.