PHASE-I CLINICAL-TRIAL OF PERILLYL ALCOHOL ADMINISTERED DAILY

Perillyl alcohol (POH; NSC-641066), a naturally occurring monoterpene, has shown antitumor and preventive activity in preclinical studies in rodent models. Drug-related activities that have been observed includ e the induction of apoptosis, cell cycle arrest, the inhibition of pos ttranslational modification of proteins that are involved in signal tr ansduction, and differential gene regulation, We treated 18 patients w ho had advanced malignancies with POH, which was given on a continuous three-times-a-day schedule at the following doses: (a) level 1 (L1), 800 mg/m(2)/dose; (b) level 2 (L2), 1600 mg/m(2)/dose; and (c) level 3 (L3), 2400 mg/m(2)/dose. The main toxicity, which seemed to be dose r elated, was gastrointestinal and included nausea and vomiting, anorexi a, unpleasant taste, satiety, and eructation. Two heavily pretreated o varian cancer patients experienced reversible greater than or equal to grade 3 granulocytopenia. Grade 1-2 fatigue was also noted. The paren t drug was not detectable in the plasma. The mean peak plasma levels o f the two main metabolites on days 1 and 29 were 175 and 139 mu M (L1) , 472 and 311 mu M (L2), and 456 and 257 mu M (L3) for perillic acid ( PA) and 7.1 and 9.8 mu M (L1), 34.2 and 34.0 mu M (L2), and 26.2 and 2 3.4 mu M (L3) for dihydroperillic acid (DHPA), Peak levels were noted 2-3 h postingestion for PA and 3-5 h postingestion for DHPA., Metaboli te half-lives measured about 2 h for each. POH, PA, and DHPA were dete ctable in the urine of all patients at L3, About 9% of the total dose was recovered in the first 24 h., The majority was recovered as PA; le ss than 1% was recovered as POH, Disease stabilization for greater tha n or equal to 6 months was seen, although no objective tumor responses were noted. Further study of POH continues with a more frequent dosin g schedule.