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Phase I trial of perillyl alcohol administered four times daily continuously

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Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

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.

Experimental design

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.

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Abbreviations

AUC:

Area under the curve

DHPA:

Dihydroperillic acid

DLT:

Dose-limiting toxicity

IGF:

Insulin-like growth factor

M6P:

Mannose-6-phosphate

MTD:

Maximum tolerated dose

PA:

Perillic acid

POH:

Perillyl alcohol

TGF:

Transforming growth factor

ULN:

Upper limit of normal

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Authors and Affiliations

  1. University of Wisconsin Comprehensive Cancer Center, 600 Highland Ave K4/601, Madison, Wisconsin, 53792, USA

    Sherry Morgan-Meadows, Sarita Dubey, Michael Gould, Kendra Tutsch, Rebecca Marnocha, Rhoda Arzoomanin, Dona Alberti, Kimberly Binger, Chris Feierabend, Jennifer Volkman, Shawna Ellingen, Sandra Black, Marcia Pomplun, George Wilding & Howard Bailey

Authors
  1. Sherry Morgan-Meadows
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  2. Sarita Dubey
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  3. Michael Gould
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  4. Kendra Tutsch
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  5. Rebecca Marnocha
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  6. Rhoda Arzoomanin
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  7. Dona Alberti
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  8. Kimberly Binger
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  9. Chris Feierabend
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  10. Jennifer Volkman
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  11. Shawna Ellingen
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  12. Sandra Black
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  13. Marcia Pomplun
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  14. George Wilding
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  15. Howard Bailey
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Corresponding author

Correspondence to Sherry Morgan-Meadows.

Additional information

This work was supported by University of Wisconsin General Clinical Research Center Grant M01 RR 03186.

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Morgan-Meadows, S., Dubey, S., Gould, M. et al. Phase I trial of perillyl alcohol administered four times daily continuously. Cancer Chemother Pharmacol 52, 361–366 (2003). https://doi.org/10.1007/s00280-003-0684-y

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  • DOI: https://doi.org/10.1007/s00280-003-0684-y

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