A phase I, pharmacokinetic (PK), and pharmacodynamic (PD) study of the farnesyl transferase inhibitor (FTI) R115777 in combination with weekly paclitaxel in patients (pts) with advanced solid cancers

Abstract

3136 Background: R115777 (tipifarnib, ZARNESTRA), an oral methyl quinolinone selectively inhibits farnesyl transferase, a critical enzyme in several cell signal transduction pathways. The preclinical synergism of FTIs with taxanes and the antitumor activity of R115777 in breast cancer provided the rationale for evaluating this regimen. Methods: Pts received escalating doses of weekly paclitaxel (1 hr on days 1, 8 & 15 every 4 weeks) and a fixed dose of R115777 (200 mg po BID) administered for 21 days followed by 7 days rest. This study also sought to evaluate whether inhibition of protein farnesylation could be detected using the chaperone protein HDJ2 as a PD surrogate of effect in peripheral blood mononuclear cells (PBMCs). Results: Thus far, 15 pts stratified by prior myelotoxic therapy into heavily (HP) and lightly pretreated (LP) cohorts (median age 57 [range 32–77], males/females-5/10) have received a total of 75 courses [range 1–14 per pt] at dosages of 60, 75, 80 and 90 mg/m2 of paclitaxel. At 90 mg/m2 of paclitaxel DLTs occurred in 2 HP pts (febrile neutropenia, grade 3 diarrhea/fatigue) and in 1 LP pt (febrile neutropenia). Non-dose-limiting neutropenia (grade 3), stomatitis, fatigue, diarrhea, and rash, have also been observed. Preliminary PK analysis of paclitaxel (with/without R115777) in 8 pts at 60 and 75 mg/m2 shows no significant difference in Cmax or AUC, when performing a paired analysis of individual pt parameters. The mean trough R115777 concentration following repeated doses was 211 ng/mL. The proportion of unfarnesylated HDJ2 increased with treatment in 5/5 evaluable pts at 75 and 90 mg/m2 of paclitaxel. Two HP pts (1 with breast, 1 with squamous cell skin cancer) remain on study with stable disease (SD) at 14 and 8 courses, respectively. Further treatment of HP/LP pts continues at 80 mg/m2 and 90 mg/m2of paclitaxel, respectively. Conclusions: The combination of R115777 and paclitaxel appears safe and feasible, with biologically relevant concentrations of R115777 and evidence of consistent inhibition of protein farnesylation in PBMCs. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Johnson and Johnson Pharmaceutical Research and Development Johnson and Johnson Pharmaceutical Research and Development Johnson and Johnson Pharmaceutical Research and Development Johnson and Johnson Pharmaceutical Research and Development