title: Phase I trial of perillyl alcohol administered four times daily continuously.
abstract: OBJECTIVE
  Previous experience with perillyl alcohol (POH) was with a formulation of 500-mg capsules each containing 250 mg POH and soybean oil. This formulation resulted in the ingestion of large amounts of soybean oil (>10 g/day). Dose-limiting toxicities (DLT) were primarily gastrointestinal. Prior studies also showed no further increase in POH metabolite concentrations with doses of >1600 mg/m2. Therefore, a new formulation of POH was developed (700 mg containing 675 mg POH) in an effort to improve dose and metabolite concentrations delivered and toxicity encountered with chronic dosing.
  
  
  METHODS
  Eligible patients had refractory solid malignancies. Dose escalation occurred in cohorts of three at the dose levels/dose of 1350 mg, 2025 mg, 2700 mg, 3375 mg and 4050 mg, administered orally four times a day in a 28-day cycle.
  
  
  RESULTS
  A group of 19 patients were enrolled. One DLT occurred at dose level 5. This cohort was expanded to six patients, and no further DLT occurred. The maximum tolerated dose was not reached. The predominant toxicity was gastrointestinal. Nausea and vomiting occurred in 63% of patients (12/19, grade 1 in 10). The same proportion of patients (12/19) experienced heartburn and indigestion, primarily grade 1. Although the side effects were mild in nature, three patients withdrew from treatment, citing intolerable gastrointestinal toxicity. The AUCs of POH metabolites did not appear to increase from level 1 to level 2 or change significantly from day 1 to day 29. Inter- and intrapatient variability in metabolite levels was observed.
  
  
  CONCLUSIONS
  This reformulation of POH appears to be an improvement upon the prior formulation, by reducing the number of capsules ingested and the degree of gastrointestinal toxicity per dose. It does not appear to offer any metabolite pharmacokinetic advantage. A dose of 2050 mg administered four times daily was easily tolerated. Higher doses can be administered but with increasing gastrointestinal toxicity that limits compliance.
authors.affiliation: University of Wisconsin Comprehensive Cancer Center, 600 Highland Ave K4/601, Madison, Wisconsin 53792, USA. slm@medicine.wisc.edu
authors.forename: Sherry
authors.initials: S
authors.lastname: Morgan-Meadows
authors.forename: Sarita
authors.initials: S
authors.lastname: Dubey
authors.forename: Michael
authors.initials: M
authors.lastname: Gould
authors.forename: Kendra
authors.initials: K
authors.lastname: Tutsch
authors.forename: Rebecca
authors.initials: R
authors.lastname: Marnocha
authors.forename: Rhoda
authors.initials: R
authors.lastname: Arzoomanin
authors.forename: Dona
authors.initials: D
authors.lastname: Alberti
authors.forename: Kimberly
authors.initials: K
authors.lastname: Binger
authors.forename: Chris
authors.initials: C
authors.lastname: Feierabend
authors.forename: Jennifer
authors.initials: J
authors.lastname: Volkman
authors.forename: Shawna
authors.initials: S
authors.lastname: Ellingen
authors.forename: Sandra
authors.initials: S
authors.lastname: Black
authors.forename: Marcia
authors.initials: M
authors.lastname: Pomplun
authors.forename: George
authors.initials: G
authors.lastname: Wilding
authors.forename: Howard
authors.initials: H
authors.lastname: Bailey
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D039821:Monoterpenes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D009369:Neoplasms / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D039821:Monoterpenes; C032208:perillyl alcohol