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Phase I pharmacokinetic trial of perillyl alcohol (NSC 641066) in patients with refractory solid malignancies
G R Hudes1, C E Szarka, A Adams
1Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. g_hudes@fccc.edu
Abstract:
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 beta pathway and/or inhibition of p21ras 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 (Cmax) values increased with dose and exhibited high intersubject variability. Day 15 DHPA Cmax values ranged from a mean +/- SD of 22.6+/-12 microM at 1600 mg/m2/dose to 42.4+/-15.24 microM at 2800 mg/m2/dose. Corresponding mean +/- SD Cmax values for PA were 433.2+/-245.8 and 774.1+/-439.6 microM. 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 p21ras, 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 p21ras 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 p21ras function in humans is not likely to occur after POH administration at safe doses of the present oral formulation.
Insights
Perillyl alcohol (POH) shows antitumor potential, but its oral administration in humans led to dose-limiting nausea and fatigue. Its metabolites, dihydroperillic acid (DHPA) and perillic acid (PA), were detected, but POH did not inhibit p21ras signaling at safe doses.
Area of Science:
- Oncology
- Pharmacology
- Cancer Therapeutics
Background:
- Perillyl alcohol (POH), a monoterpene, exhibits anticarcinogenic and antitumor properties in preclinical models.
- Potential mechanisms involve the transforming growth factor beta pathway and p21ras signaling inhibition, inducing differentiation or apoptosis.
Purpose of the Study:
- To evaluate the safety, tolerability, and pharmacokinetic profile of oral Perillyl alcohol (POH) in a Phase I clinical trial.
- To assess the impact of POH on p21ras signaling pathway markers in cancer patients.
Main Methods:
- A Phase I dose-escalation trial administering POH orally (1600-2800 mg/m2) three times daily for 14 days per 28-day cycle.
- Pharmacokinetic analysis of POH metabolites (DHPA, PA) in plasma and urine.
- Evaluation of p21ras, rap1, and rhoA expression in peripheral blood mononuclear cells.
Main Results:
- Chronic nausea and fatigue were dose-limiting toxicities at 2800 mg/m2; hypokalemia was observed at higher doses.
- POH was not detected in plasma, but its metabolites DHPA and PA were measurable with dose-dependent increases and high intersubject variability.
- No consistent inhibition of p21ras signaling was observed in patient cells or in vitro at relevant concentrations.
Conclusions:
- Oral POH at 1600-2100 mg/m2 is well-tolerated on a 14-day on/14-day off schedule.
- Inhibition of p21ras function is unlikely with the current oral formulation at safe doses.
- Further investigation into POH's therapeutic potential may require alternative formulations or administration routes.