title: A phase I trial of perillyl alcohol in patients with advanced solid tumors.
abstract: OBJECTIVE
  Perillyl alcohol is a plant-derived lipid with preclinical antitumor activity. Its proposed mechanism of action involves inhibition of post-translational isoprenylation of small G proteins, including the proto-oncogene p21- ras, thereby blocking signal transduction. This phase I trial was conducted to determine the optimal dose of perillyl alcohol.
  
  
  METHODS
  The study group comprised 21 adults with advanced solid tumors who were treated with perillyl alcohol, delivered orally, four times daily, without interruption. Doses ranged from 4,800 to 11,200 mg/m(2) per day.
  
  
  RESULTS
  The maximum tolerated dose (MTD) for this schedule was determined to be 8400 mg/m(2) per day. The dose-limiting toxicities in this trial were nausea and vomiting, encountered in all patients at the highest dose level. No antitumor activity was observed. Pharmacokinetic data suggest dose-dependent increases in C(max) of perillic acid, a metabolite of perillyl alcohol, but with high inter- and intrapatient variability.
  
  
  CONCLUSIONS
  The MTD of perillyl alcohol for this schedule was determined to be 8400 mg/m(2) per day. This is higher than the MTDs determined in other similar phase I trials. This may have been due to the fact that the gastrointestinal symptoms caused by perillyl alcohol are highly subjective, with high interpatient variability. Phase II trials of perillyl alcohol in hormone-refractory prostate, breast, ovarian and colorectal cancer using doses in the range 4800-6400 mg/m(2) per day are underway.
authors.affiliation: Department of Medicine, Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. azzolic@mskcc.org
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Azzoli
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Ng
authors.forename: Lee M
authors.initials: LM
authors.lastname: Krug
authors.forename: David R
authors.initials: DR
authors.lastname: Spriggs
authors.forename: William P
authors.initials: WP
authors.lastname: Tong
authors.forename: Elyn R
authors.initials: ER
authors.lastname: Riedel
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D039821:Monoterpenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000090063:Proto-Oncogene Mas; D011795:Surveys and Questionnaires; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; D039821:Monoterpenes; D000090063:Proto-Oncogene Mas; C032208:perillyl alcohol