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Phase I Pharmacokinetic Trial of Perillyl Alcohol (NSC 641066) in Patients with Refractory Solid Malignancies¹

Departments of Medical Oncology [G. R. H., C. E. S., S. R., R. A. M., L. M. W., C. J. L., G. Y., T. H.], Pharmacology [A. A., M. Q., J. M. G.], and Biostatistics [S. L.], Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111

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 ß 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/m²/dose, with escalations to 2100 and 2800 mg/m²/dose in subsequent cohorts. Chronic nausea and fatigue were dose-limiting toxic effects at 2800 mg/m². Grade 1–2 hypokalemia was common at 2100 and 2800 mg/m². 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 µM at 1600 mg/m²/dose to 42.4 ± 15.24 µM at 2800 mg/m²/dose. Corresponding mean ± SD C_max values for PA were 433.2 ± 245.8 and 774.1 ± 439.6 µM. One patient treated at the 2800 mg/m²/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/m² 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.

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