A phase I trial of perillyl alcohol administered four times daily for 14 days out of 28 days

Howard H. Bailey, George Wilding, Kendra D. Tutsch, Rhoda Z. Arzoomanian, Dona Alberti, Chris Feierabend, Kris Simon, Rebecca Marnocha, Sarah A. Holstein, Jan Stewart, Kriste A. Lewis, Raymond Hohl

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Abstract

Purpose: 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 β (TGFβ) 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 TGFβ 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/m2 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 TGFβ 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/m2 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/m2 per dose were approximately 600 μM (PA) and 50 μM (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 TGFβ 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.

Original languageEnglish (US)
Pages (from-to)368-376
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume54
Issue number4
DOIs
StatePublished - Oct 1 2004

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perilla alcohol
Transforming Growth Factors
Pharmacokinetics
Toxicity
Plasmas
Lymphocytes
Metabolites
Appointments and Schedules
Blood
ras Proteins
Hypokalemia

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Bailey, Howard H. ; Wilding, George ; Tutsch, Kendra D. ; Arzoomanian, Rhoda Z. ; Alberti, Dona ; Feierabend, Chris ; Simon, Kris ; Marnocha, Rebecca ; Holstein, Sarah A. ; Stewart, Jan ; Lewis, Kriste A. ; Hohl, Raymond. / A phase I trial of perillyl alcohol administered four times daily for 14 days out of 28 days. In: Cancer Chemotherapy and Pharmacology. 2004 ; Vol. 54, No. 4. pp. 368-376.
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title = "A phase I trial of perillyl alcohol administered four times daily for 14 days out of 28 days",
abstract = "Purpose: 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 β (TGFβ) 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 TGFβ 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/m2 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 TGFβ 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/m2 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/m2 per dose were approximately 600 μM (PA) and 50 μM (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 TGFβ 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.",
author = "Bailey, {Howard H.} and George Wilding and Tutsch, {Kendra D.} and Arzoomanian, {Rhoda Z.} and Dona Alberti and Chris Feierabend and Kris Simon and Rebecca Marnocha and Holstein, {Sarah A.} and Jan Stewart and Lewis, {Kriste A.} and Raymond Hohl",
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Bailey, HH, Wilding, G, Tutsch, KD, Arzoomanian, RZ, Alberti, D, Feierabend, C, Simon, K, Marnocha, R, Holstein, SA, Stewart, J, Lewis, KA & Hohl, R 2004, 'A phase I trial of perillyl alcohol administered four times daily for 14 days out of 28 days', Cancer Chemotherapy and Pharmacology, vol. 54, no. 4, pp. 368-376. https://doi.org/10.1007/s00280-004-0788-z

A phase I trial of perillyl alcohol administered four times daily for 14 days out of 28 days. / Bailey, Howard H.; Wilding, George; Tutsch, Kendra D.; Arzoomanian, Rhoda Z.; Alberti, Dona; Feierabend, Chris; Simon, Kris; Marnocha, Rebecca; Holstein, Sarah A.; Stewart, Jan; Lewis, Kriste A.; Hohl, Raymond.

In: Cancer Chemotherapy and Pharmacology, Vol. 54, No. 4, 01.10.2004, p. 368-376.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A phase I trial of perillyl alcohol administered four times daily for 14 days out of 28 days

AU - Bailey, Howard H.

AU - Wilding, George

AU - Tutsch, Kendra D.

AU - Arzoomanian, Rhoda Z.

AU - Alberti, Dona

AU - Feierabend, Chris

AU - Simon, Kris

AU - Marnocha, Rebecca

AU - Holstein, Sarah A.

AU - Stewart, Jan

AU - Lewis, Kriste A.

AU - Hohl, Raymond

PY - 2004/10/1

Y1 - 2004/10/1

N2 - Purpose: 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 β (TGFβ) 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 TGFβ 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/m2 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 TGFβ 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/m2 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/m2 per dose were approximately 600 μM (PA) and 50 μM (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 TGFβ 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.

AB - Purpose: 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 β (TGFβ) 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 TGFβ 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/m2 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 TGFβ 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/m2 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/m2 per dose were approximately 600 μM (PA) and 50 μM (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 TGFβ 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.

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