Phase I Pharmacokinetic Trial of Perillyl Alcohol (NSC 641066) in Patients with Refractory Solid Malignancies

Perillyl alcohol (POH) is a monoterpene with anticarcinogenic and antitumor activity in murine tumor models. Putative mechanisms of action include activation of the transforming growth factor β 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 28-day cycle. The starting dose of POH was 1600 mg/m 2 /dose, with escalations 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 hypokalemia was common at 2100 and 2800 mg/m 2 . Although POH could not be detected in plasma, two of its metabolites, dihydroperillic acid (DHPA) and perillic 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 concentration versus time curve and peak plasma concentration ( C max ) values increased with dose and exhibited high intersubject variability. Day 15 DHPA C max values ranged from a mean ± SD of 22.6 ± 12 μ m at 1600 mg/m 2 /dose to 42.4 ± 15.24 μ m at 2800 mg/m 2 /dose. Corresponding mean ± SD C max values for PA were 433.2 ± 245.8 and 774.1 ± 439.6μ m . One patient treated at the 2800 mg/m 2 /dose had markedly prolonged plasma levels of both PA and DHPA and developed grade 3 mucositis. POH treatment did not consistently alter the expression of p21 ras , rap1, or rhoA in peripheral blood mononuclear cells obtained from patients treated at the highest dose level. The metabolites PA and DHPA did not change expression or isoprenylation of p21 ras in MCF-7 breast or DU145 prostate carcinoma cells at concentrations that exceeded those achieved in patient plasma after POH treatment. We conclude that POH at 1600–2100 mg/m 2 p.o. three times daily is well tolerated on a 14-day on/14-day off dosing schedule. Inhibition of p21 ras function in humans is not likely to occur after POH administration at safe doses of the present oral formulation.