Phase I pharmacokinetic trial of perillyl alcohol (NSC 641066) in patientswith refractory solid malignancies

Perillyl alcohol (POH) is a monoterpene with anticarcinogenic and antitumor activity in murine tumor models. Putative mechanisms of action include act ivation of the transforming growth factor beta pathway and/or inhibition of p21(ras) signaling, leading to differentiation or apoptosis, In this Phase I trial, 17 patients took POH p.o. three times daily for 14 days of each 2 8-day cycle. The starting dose of POH was 1600 mg/m(2)/dose, with escalatio ns to 2100 and 2800 mg/m(2)/dose in subsequent cohorts. Chronic nausea and fatigue were dose-limiting toxic effects at 2800 mg/m(2). Grade 1-2 hypokal emia was common at 2100 and 2800 mg/m(2), Although POH could not be detecte d in plasma, two of its metabolites, dihydroperillic acid (DHPA) and perill ic acid (PA), were measured in plasma and urine on days 1 and 15 after the first and last doses of POH, respectively. Both area under the concentratio n versus time curve and peak plasma concentration (C-max) values increased with dose and exhibited high intersubject variability. Day 15 DHPA C-max va lues ranged from a mean +/- SD of 22.6 +/- 12 mu M at 1600 mg/m(2)/dose to 42.4 +/- 15.24 mu M at 2800 mg/m(2)/dose. Corresponding mean +/- SD C-max v alues for PA were 433.2 +/- 245.8 and 774.1 +/- 439.6 mu M. One patient tre ated at the 2800 mg/m(2)/dose had markedly prolonged plasma levels of both PA and DHPA and developed grade 3 mucositis, POD treatment did not consiste ntly alter the expression of p21(ras), rap1, or rhoA in peripheral blood mo nonuclear cells obtained from patients treated at the highest dose level, T he metabolites PA and DHPA did not change expression or isoprenylation of p 21(ras) in MCF-7 breast or DU145 prostate carcinoma cells at concentrations that exceeded those achieved in patient plasma after FOR treatment, We con clude that POH at 1600-2100 mg/m(2) p.o. three times daily is well tolerate d on a 14-day on/14-day off dosing schedule. Inhibition of p21(ras) functio n in humans is not likely to occur after POH administration at safe doses o f the present oral formulation.