Phase I and pharmacokinetic study of the orally administered farnesyl transferase inhibitor R115777 in patients with advanced solid tumors

Abstract

R115777 is a novel selective inhibitor of farnesyl transferase, an enzyme that is involved in the proliferation of the malignant cell type. This study was designed to determine the toxicity, maximal tolerated dose and pharmacokinetics of R115777 when given orally b.i.d. for 28 days followed by 1-2 weeks of rest. Patients with advanced solid tumors for whom no standard therapy was available could enter the study. The starting dose of R115777 was 200 mg/dose and inter- as well as intra-patient dose escalations were performed with increments of 100 mg/dose. Nine patients entered the study and received in total 23 treatment cycles. A dose of 300 mg b.i.d. proved feasible with grade 4 neutropenia occurring in one of six patients who completed the first treatment cycle. Other toxicities were infrequent. Pharmacokinetic analysis demonstrated that peak plasma concentrations of 881+/-393 ng/ml were reached within 1-5 h. No accumulation of R115777 was observed over a 28-day period. The study was terminated based on these results together with the observation from a related phase I study in which higher doses of R115777 were associated with the frequent occurrence of grade 3-4 myelosuppression. We conclude that the recommended dose of R115777 given for 28 days followed by 1-2 weeks of rest is 300 mg b.i.d. Myelosuppression is the dose-limiting toxicity.

Effects of the farnesyl transferase inhibitor R115777 on normal and leukemic hematopoiesis

“…7 In clinical trials, the plasma concentrations of R115777 has been found to be 0.86-100 nM. 16,17 The doses inhibitory for leukemic and normal progenitors as reported here are therefore in a dose range consistent with these observations. At the doses that inhibit proliferation and are in accord with levels achievable in vivo, we were unable to measure significant effects on apoptosis as measured by annexin V, TdT endlabeling assays, or by DNA laddering assays.…”

The farnesyl transferase inhibitor, tipifarnib, is a potent inhibitor of the MDR1 gene product, P-glycoprotein, and demonstrates significant cytotoxic synergism against human leukemia cell lines

“…These results coupled with the results from pharmacokinetic studies of tipifarnib in patients with AML that received tipifarnib 600 mg twice daily demonstrate that tipifarnib is able to inhibit Pgp-mediated DNR efflux at clinically relevant concentrations. 18,23 For example, in these studies the C max and C min varied between 3 and 3.5 mM and 1.5-0.5 mM. 18,23 Although preclinical data indicate that the plasma protein binding of tipifarnib is 99.3%, 23 in vivo pharmacokinetic data suggest that these concentrations inhibit FT activity and result in antitumor effects.…”

“…18,23 For example, in these studies the C max and C min varied between 3 and 3.5 mM and 1.5-0.5 mM. 18,23 Although preclinical data indicate that the plasma protein binding of tipifarnib is 99.3%, 23 in vivo pharmacokinetic data suggest that these concentrations inhibit FT activity and result in antitumor effects. 18 Despite these similarities, tipifarnib and lonafarnib are distinct molecules that are not structurally related.…”

Farnesyl transferase inhibitor R115777 induces apoptosis of human myeloma cells

“…Pharmacokinetic studies of R115777 in patients have previously shown that concentrations of 0.5 to 10 M of R115777 were in the range of therapeutical concentrations. 3,4 Apoptosis was monitored daily by APO2.7 staining. Ten micromolars of R115777 induced significant apoptosis (Ն40% of apoptotic cells) in XG-2 and LP-1 after 48 h of treatment and in U266 after 72 h (Figure 2).…”

“…2,3 Moreover, several ongoing clinical trials have shown some efficacy of R115777 in the treatment of solid tumors and hematologic malignancies particularly in acute myeloid leukemia where preliminary results seem promising. [4][5][6][7] More generally, there is now evidence to indicate that most FTI demonstrate antitumor activity independently of the presence or absence of Ras mutations. 8,9 Indeed, in addition to Ras proteins, multiple downstream targets appear to be affected by fanesyl transferase inhibition.…”