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Phase I clinical trial of perillyl alcohol administered daily.
Clin Cancer Res 1998; 4(5):1159-64CC

Abstract

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 include the induction of apoptosis, cell cycle arrest, the inhibition of posttranslational modification of proteins that are involved in signal transduction, and differential gene regulation. We treated 18 patients who 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/m2/dose; (b) level 2 (L2), 1600 mg/m2/dose; and (c) level 3 (L3), 2400 mg/m2/dose. The main toxicity, which seemed to be dose related, was gastrointestinal and included nausea and vomiting, anorexia, unpleasant taste, satiety, and eructation. Two heavily pretreated ovarian cancer patients experienced reversible > or =grade 3 granulocytopenia. Grade 1-2 fatigue was also noted. The parent drug was not detectable in the plasma. The mean peak plasma levels of the two main metabolites on days 1 and 29 were 175 and 139 microM (L1), 472 and 311 microM (L2), and 456 and 257 microM (L3) for perillic acid (PA) and 7.1 and 9.8 microM (L1), 34.2 and 34.0 microM (L2), and 26.2 and 23.4 microM (L3) for dihydroperillic acid (DHPA). Peak levels were noted 2-3 h postingestion for PA and 3-5 h postingestion for DHPA. Metabolite half-lives measured about 2 h for each. POH, PA, and DHPA were detectable 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; less than 1% was recovered as POH. Disease stabilization for > or =6 months was seen, although no objective tumor responses were noted. Further study of POH continues with a more frequent dosing schedule.

Authors+Show Affiliations

University of Wisconsin Comprehensive Cancer Center, Madison 53792, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

9607573

Citation

Ripple, G H., et al. "Phase I Clinical Trial of Perillyl Alcohol Administered Daily." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 4, no. 5, 1998, pp. 1159-64.
Ripple GH, Gould MN, Stewart JA, et al. Phase I clinical trial of perillyl alcohol administered daily. Clin Cancer Res. 1998;4(5):1159-64.
Ripple, G. H., Gould, M. N., Stewart, J. A., Tutsch, K. D., Arzoomanian, R. Z., Alberti, D., ... Bailey, H. H. (1998). Phase I clinical trial of perillyl alcohol administered daily. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 4(5), pp. 1159-64.
Ripple GH, et al. Phase I Clinical Trial of Perillyl Alcohol Administered Daily. Clin Cancer Res. 1998;4(5):1159-64. PubMed PMID: 9607573.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phase I clinical trial of perillyl alcohol administered daily. AU - Ripple,G H, AU - Gould,M N, AU - Stewart,J A, AU - Tutsch,K D, AU - Arzoomanian,R Z, AU - Alberti,D, AU - Feierabend,C, AU - Pomplun,M, AU - Wilding,G, AU - Bailey,H H, PY - 1998/6/2/pubmed PY - 1998/6/2/medline PY - 1998/6/2/entrez SP - 1159 EP - 64 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 4 IS - 5 N2 - 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 include the induction of apoptosis, cell cycle arrest, the inhibition of posttranslational modification of proteins that are involved in signal transduction, and differential gene regulation. We treated 18 patients who 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/m2/dose; (b) level 2 (L2), 1600 mg/m2/dose; and (c) level 3 (L3), 2400 mg/m2/dose. The main toxicity, which seemed to be dose related, was gastrointestinal and included nausea and vomiting, anorexia, unpleasant taste, satiety, and eructation. Two heavily pretreated ovarian cancer patients experienced reversible > or =grade 3 granulocytopenia. Grade 1-2 fatigue was also noted. The parent drug was not detectable in the plasma. The mean peak plasma levels of the two main metabolites on days 1 and 29 were 175 and 139 microM (L1), 472 and 311 microM (L2), and 456 and 257 microM (L3) for perillic acid (PA) and 7.1 and 9.8 microM (L1), 34.2 and 34.0 microM (L2), and 26.2 and 23.4 microM (L3) for dihydroperillic acid (DHPA). Peak levels were noted 2-3 h postingestion for PA and 3-5 h postingestion for DHPA. Metabolite half-lives measured about 2 h for each. POH, PA, and DHPA were detectable 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; less than 1% was recovered as POH. Disease stabilization for > or =6 months was seen, although no objective tumor responses were noted. Further study of POH continues with a more frequent dosing schedule. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/9607573/Phase_I_clinical_trial_of_perillyl_alcohol_administered_daily_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=9607573 DB - PRIME DP - Unbound Medicine ER -