title: A phase I trial of perillyl alcohol administered four times daily for 14 days out of 28 days.
abstract: OBJECTIVE
  Perillyl alcohol (POH) has been shown to have both chemopreventative and chemotherapeutic activities in preclinical studies. The underlying mechanism(s) of action of POH have yet to be delineated but may involve effects on the transforming growth factor beta (TGFbeta) and/or the Ras signaling pathways. A phase I study of POH for 14 days out of every 28 days in subjects with advanced malignancies was performed to evaluate dose escalation, toxicity, pharmacokinetics, and effects on TGFbeta and Ras.
  
  
  METHODS
  POH was administered orally (500 mg capsules containing 250 mg POH) to 20 patients four times a day on a continuous basis for 14 days followed by a 14-day rest period, for up to three courses. The starting dose was 1200 mg/m(2) per dose. A minimum of three patients were treated and evaluated at each escalating POH dose. Pharmacokinetic analysis was performed on days 1 and 14 of course 1 and day 1 of selected later courses. Plasma TGFbeta levels were measured on days 1 and 14. Peripheral blood lymphocyte (PBLs) Ras levels were assayed on days 1 and 2 of the first course.
  
  
  RESULTS
  The 20 patients, of whom 15 were evaluable, received doses between 1200 and 2000 mg/m(2) per dose for a total of 43 courses. The most common observed toxicities were nausea, gastrointestinal distress, and fatigue. Other toxicities included diarrhea or constipation, hypokalemia, and one incidence of acute pancreatitis. Due to these toxicities, four of the patients declined further treatment either during or after the second course. While POH was not detected in plasma, perillic acid (PA) and dihydroperillic acid (DHPA) were detected in plasma, and the peak levels at 2000 mg/m(2) per dose were approximately 600 micro M (PA) and 50 micro M (DHPA). There was some evidence for linearity in the peak plasma levels and area under the concentration-time curve of the metabolites from the starting dose to the highest dose. Metabolite pharmacokinetics were not significantly affected by ingestion in the fed or fasting state, or repeated exposure to POH. No evidence for an effect of POH on plasma TGFbeta or PBL Ras protein was observed. No objective responses were observed.
  
  
  CONCLUSIONS
  In adults with advanced malignancies, an interrupted administration schedule of POH did not reveal significant advantages over continuous dosing schedules.
authors.affiliation: University of Wisconsin Comprehensive Cancer Center, K6/568 CSC, 600 Highland Avenue, Madison, WI 53792-5669, USA. hhbailey@facstaff.wisc.edu
authors.forename: Howard H
authors.initials: HH
authors.lastname: Bailey
authors.forename: George
authors.initials: G
authors.lastname: Wilding
authors.forename: Kendra D
authors.initials: KD
authors.lastname: Tutsch
authors.forename: Rhoda Z
authors.initials: RZ
authors.lastname: Arzoomanian
authors.forename: Dona
authors.initials: D
authors.lastname: Alberti
authors.forename: Chris
authors.initials: C
authors.lastname: Feierabend
authors.forename: Kris
authors.initials: K
authors.lastname: Simon
authors.forename: Rebecca
authors.initials: R
authors.lastname: Marnocha
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Holstein
authors.forename: Jan
authors.initials: J
authors.lastname: Stewart
authors.forename: Kriste A
authors.initials: KA
authors.lastname: Lewis
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Hohl
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D039821:Monoterpenes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D009369:Neoplasms
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D039821:Monoterpenes; C032208:perillyl alcohol